jag009
★★★

NJ,
2022-09-02 00:16
(99 d 01:34 ago)

Posting: # 23258
Views: 1,590
 

 US (or EU) ANDA: Fail f2 but pass BE? [Regulatives / Guidelines]

Hi all,

A question, has anyone ever filed an ANDA with great BE study results (90% Cmax and AUC ~ 98-100%, adequate sample size, ISCV~25%) but with f2 << 50 (F2=30 due to differences in very early timepts) in the comparative dissolution study based on method recommended in the BE guidance for IR product?

1) F2 is not really applicable for IR, correct? The sampling timepts were 5, 10 ,20, 30, 45mins. I know that f2 is not really relevant if % dissolve > 85% in 15 mins, but my product is >85% after 20 mins..
2) is f2 based on guidance recommendation even relevant if the BE results are so good?

Thx
john
wienui
★    

Germany/Oman,
2022-09-02 01:22
(99 d 00:29 ago)

@ jag009
Posting: # 23259
Views: 1,393
 

 US (or EU) ANDA: Fail f2 but pass BE?

Hi John & all,

❝ A question, has anyone ever filed an ANDA with great BE study results (90% Cmax and AUC ~ 98-100%, adequate sample size, ISCV~25%) but with f2 << 50 (F2=30 due to differences in very early timepts) in the comparative dissolution study based on method recommended in the BE guidance for IR product?


normally, In vivo study over­rules in vitro dissolution study i.e, even if f2 doesn't show the similarity between the test & reference formulations, the two formulations are considered as therapeutic equivalence.

❝ 1) F2 is not really applicable for IR, correct? The sampling timepts were 5, 10 ,20, 30, 45mins. I know that f2 is not really relevant if % dissolve > 85% in 15 mins, but my product is >85% after 20 mins..


What about if you start with sampling time points @ 10 min ( EMA) and not @ 5min ( FDA)?
have you tried with bootstrapping to overcome the high variability in the early sampling time points?

❝ 2) is f2 based on guidance recommendation even relevant if the BE results are so good?


f2 is a supportive in vitro method to the in Vivo crucial BE study to prove the therapeutic equivalence.

Cheers,
Osama
jag009
★★★

NJ,
2022-09-02 02:29
(98 d 23:22 ago)

@ wienui
Posting: # 23260
Views: 1,372
 

 US (or EU) ANDA: Fail f2 but pass BE?

Thanks Osama.

That's my thinking as well since the BE studies were ~ 100% in ratios and reasonably sized.
But explaining to those non-pk/bioparm management f**ls who keep asking for risk assessment BS is a challenge.

❝ What about if you start with sampling time points @ 10 min ( EMA) and not @ 5min ( FDA)?

❝ have you tried with bootstrapping to overcome the high variability in the early sampling time points?


Unfortunately the guidance asked for 5 and 10 mins and on... evaluating the data now to see if there is need to evaluate..

john
dshah
★★  

India/United Kingdom,
2022-09-02 13:37
(98 d 12:13 ago)

@ jag009
Posting: # 23261
Views: 1,354
 

 US (or EU) ANDA: Fail f2 but pass BE?

Hi John!

I think the talk is about BE strength only, but what about other strength waiver?

Regards,
Divyen Shah
jag009
★★★

NJ,
2022-09-05 01:13
(96 d 00:37 ago)

@ dshah
Posting: # 23267
Views: 1,305
 

 US (or EU) ANDA: Fail f2 but pass BE?

HI Divyen,

❝ I think the talk is about BE strength only, but what about other strength waiver?

You meant if f2 fails between strengths for a strength waiver?

John
dshah
★★  

India/United Kingdom,
2022-09-05 13:16
(95 d 12:34 ago)

@ jag009
Posting: # 23269
Views: 1,271
 

 US (or EU) ANDA: Fail f2 but pass BE?

Hi John!
You guess it right John.
Kindly refer below PSG for example.
[image]
So, if only BE strength is in the focus, there is no need to worry.
Regards,
Divyen
wienui
★    

Germany/Oman,
2022-09-06 01:29
(95 d 00:21 ago)

@ dshah
Posting: # 23270
Views: 1,219
 

 US (or EU) ANDA: Fail f2 but pass BE?

Hi Divyen,

❝ You guess it right John.

❝ Kindly refer below PSG for example.

[image]


I think you have asked this question several times and we have discussed it before, for example here:

https://forum.bebac.at/mix_entry.php?id=21680#p21742

and here
https://forum.bebac.at/mix_entry.php?id=22747#p22768

By the way, I will hold a presentation at The 4th MENA Regulatory Conference on Bioequivalence, Biowaivers, Bioanalysis, and Dissolution about this topic on September 19th, 2022, in Amman, Jordan.

"Additional strength Biowaiver: Practical Regulatory Similarities & Differences Approaches"


http://rbbbd.com/IPRC_Program.aspx

Cheers,
Osama
dshah
★★  

India/United Kingdom,
2022-09-06 02:49
(94 d 23:02 ago)

@ wienui
Posting: # 23272
Views: 1,216
 

 US (or EU) ANDA: Fail f2 but pass BE?

Dear Osama!
I was not asking the question but suggesting to focus on other strength waiver as well.
Regards,
Divyen
jag009
★★★

NJ,
2022-09-08 21:32
(92 d 04:18 ago)

@ dshah
Posting: # 23280
Views: 1,125
 

 US (or EU) ANDA: Fail f2 but pass BE?

Hi,

❝ You guess it right John.


If you fail f2 comparison between highest and lowest (or other) strengths then they wont grant you the waiver unless you run bio, even if you claim formulations are proportional.

John
dshah
★★  

India/United Kingdom,
2022-09-09 19:56
(91 d 05:55 ago)

@ jag009
Posting: # 23290
Views: 1,089
 

 US (or EU) ANDA: Fail f2 but pass BE?

Hi John!

❝ If you fail f2 comparison between highest and lowest (or other) strengths then they wont grant you the waiver unless you run bio, even if you claim formulations are proportional.


You can try multi tablet for dissolution, or perform bootstrap for f2, try model dependent and independent approaches to prove similarity in dissolution.

Regards,
Divyen
dshah
★★  

India/United Kingdom,
2022-09-15 13:09
(85 d 12:41 ago)

@ jag009
Posting: # 23296
Views: 934
 

 US (or EU) ANDA: Fail f2 but pass BE?

Hi John!
Below decision tree might help you.
[image]
Regards,
Divyen
Rayhope
☆    

India,
2022-09-15 17:13
(85 d 08:38 ago)

@ dshah
Posting: # 23298
Views: 900
 

 US (or EU) ANDA: Fail f2 but pass BE?

❝ Below decision tree might help you.

[image]


HI Divyen ,
Please let me know from where u got this flow chart. Please name the guidance will be helpfull.
dshah
★★  

India/United Kingdom,
2022-09-20 18:02
(80 d 07:48 ago)

@ Rayhope
Posting: # 23309
Views: 796
 

 US (or EU) ANDA: Fail f2 but pass BE?

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