jag009
★★★

NJ,
2022-01-24 07:48
(156 d 10:01 ago)

Posting: # 22747
Views: 1,133
 

 biowaiver for higher strength [Regulatives / Guidelines]

Hi folks,

A weird question about an immediate release product.
If I have
1) A BE study showing BE between a test and a reference at lower strength
2) A higher strength test product that is formulation proportional to the lower strength test product but the strengths are not interchangeable (meaning for example the lower strength product is 160 mg and the higher strength product is 500 mg).
3) Dissolution test lower vs higher strengths f2> 50.
4) I have efficacy and safety data for a reference product. Same molecule, immediate release and same strength as the highest strength test product.

Based on the above, can I file a biowaiver for the higher strength test product so I don't have to run a PK BE study?

This is an NDA.

Thanks
John
dshah
★    

India/United Kingdom,
2022-01-24 11:01
(156 d 06:48 ago)

@ jag009
Posting: # 22750
Views: 974
 

 biowaiver for higher strength

Hi John!
Interesting question but when we revisit guidelines, the biowaiver recommendation is mostly for lower strength formulation only. I believe that the criteria of not using higher strength due to safety/AE if justifiable, then may be used to support waiver using lower strength.
Regards,
Dshah
jag009
★★★

NJ,
2022-01-24 15:09
(156 d 02:40 ago)

@ dshah
Posting: # 22753
Views: 964
 

 biowaiver for higher strength

HI Dshah,

» Interesting question but when we revisit guidelines, the biowaiver recommendation is mostly for lower strength formulation only. I believe that the criteria of not using higher strength due to safety/AE if justifiable, then may be used to support waiver using lower strength.

According to the guidance it seems possible.
"For an NDA, biowaivers of a higher strength will be determined to be appropriate based on (1) clinical safety and/or efficacy studies including data on the dose and the desirability of the higher strength, (2) linear elimination kinetics over the therapeutic dose range, (3) the higher strength being proportionally similar to the lower strength, and (4) the same dissolution procedures being used for both strengths and similar dissolution results obtained. A dissolution profile should be generated for all strengths."

thx
John
dshah
★    

India/United Kingdom,
2022-01-24 20:18
(155 d 21:31 ago)

@ jag009
Posting: # 22755
Views: 927
 

 biowaiver for higher strength

Thank you John!
So what was the rational for conducting BE on lower strength rather than higher strength?
Regards,
Dshah
dshah
★    

India/United Kingdom,
2022-02-03 19:07
(145 d 22:43 ago)

@ jag009
Posting: # 22771
Views: 716
 

 biowaiver for higher strength

Hi John!
From the guideline- "The higher strengths of the test and reference products are proportionally similar to their corresponding lower strength" could be important as if the lower strength 160 mg and higher strength 500 mg are not interchangeable.
Regards,
Dshah
Ohlbe
★★★

France,
2022-01-24 12:16
(156 d 05:34 ago)

@ jag009
Posting: # 22751
Views: 975
 

 Linearity

Hi John,

Does your drug show linear PK ? If not: does it show more-than-proportional increase (then the highest strength would be more sensitive to show differences in BA) or less-than-proportional increase (lowest strength would be more sensitive, giving you good arguments) ?

Regards
Ohlbe
jag009
★★★

NJ,
2022-01-24 15:06
(156 d 02:43 ago)

@ Ohlbe
Posting: # 22752
Views: 956
 

 Linearity

Hi Ohlbe,

» Does your drug show linear PK ? If not: does it show more-than-proportional increase (then the highest strength would be more sensitive to show differences in BA) or less-than-proportional increase (lowest strength would be more sensitive, giving you good arguments) ?

Yes its linear PK. I read the FDA guidance about Guidance, for NDA it seeems "possible" as long as one can provide safety and efficacy data.

John
wienui
★    

Germany/Oman,
2022-02-01 09:12
(148 d 08:37 ago)

(edited by wienui on 2022-02-01 15:29)
@ jag009
Posting: # 22768
Views: 809
 

 biowaiver for higher strength

Hi John,

» Based on the above, can I file a biowaiver for the higher strength test product so I don't have to run a PK BE study?

Are both strengths (low & high) follow the following EMA 5% & exceients rule?

EMA :
Amount of API must be < 5% of tablet core weight, and
Amounts of excipients are same per strength, or
Only the amount of a filler is changed to account for changes in API weight.

Cheers,
Osama
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