dshah
★

India/United Kingdom,
2020-07-13 08:09
(761 d 18:57 ago)

Posting: # 21680
Views: 2,503

## Biowaiver for lower strength using different OGD media [Dissolution / BCS / IVIVC]

Greetings All!
Hope all are doing well and are safe in this pandemic condition.
We are working on a NTI drug with high variability for which different dissolution media is recommended by USFDA.
For BE study as per USFDA- a fasting and fed study for highest strength is recommended.
For EMA- A fed study on highest strength and a fasting study on another mid strength is concluded based on guideline.
For waiver request for other strength we need acceptable in vitro dissolution testing of all strengths. Generally media for lower and higher strength are same but in my condition, due to solubility limitations, highest strength's dissolution is recommended with 0.45% SDS, a mid range strength's dissolution with 0.2% SDS and lower strength dissolution using no surfactant are recommended.
A screenshot is attached for reference.
In such condition- how to prove F2 value>50 for rest of the strength because recommended media are different?
Regards,
Shah
Helmut
★★★

Vienna, Austria,
2020-07-15 19:08
(759 d 07:57 ago)

@ dshah
Posting: # 21704
Views: 2,215

## EMA: No biowaivers for NTIDs

Hi dshah,

» We are working on a NTI drug with high variability for which different dissolution media is recommended by USFDA.
» For BE study as per USFDA- a fasting and fed study for highest strength is recommended.

Why don’t you simply tell us that the drug is rivaroxaban?

» For EMA- A fed study on highest strength and a fasting study on another mid strength is concluded based on guideline.

Fine. Though there is no product-specific guidance for rivaroxaban publishd by the EMA, most people would consider it an NTID indeed. Following the logic of other NTID-guidances that would mean acceptance limits of 80.00–125.00% for Cmax and 90.00–111.11% for AUC. In rare cases the limits of Cmax have to narrowed as well. Up to you to provide a justification.

» For waiver request for other strength we need acceptable in vitro dissolution testing of all strengths.

Biowaivers for NTIDs are not acceptable. BE-Guideline APPENDIX III:

Applying for a BCS-based biowaiver is restricted to highly soluble drug substances with known human absorption and considered not to have a narrow therapeutic index.

Dif-tor heh smusma 🖖
Helmut Schütz

The quality of responses received is directly proportional to the quality of the question asked. 🚮
Science Quotes
Relaxation
★

Germany,
2020-07-16 10:54
(758 d 16:12 ago)

@ Helmut
Posting: # 21707
Views: 2,169

## EMA: No biowaivers for NTIDs

Hello everyone.

Just to complement the answer quickly.
There actually is a product-specific guidance for rivaroxaban. I hope that I do not mix something up, but it currently seems valid.
Its just not considering it as an NTI as the recommended acceptance range is not narrowed in accordance with the basic BE-Guideline.

https://www.ema.europa.eu/en/rivaroxaban-product-specific-bioequivalence-guidance

Note: other authorities see this differently.

Best regards,
Steven.
Helmut
★★★

Vienna, Austria,
2020-07-16 11:27
(758 d 15:39 ago)

@ Relaxation
Posting: # 21710
Views: 2,190

## Biowaiver only for BCS I and – under certain conditions – BCS III drugs

Hi Steven,

THX! I was not aware of this one (should have searched my own guideline collection).

@dshah

BCS Classification  BCS Class: ☐ I  ☐ III   Neither of the two
                    Background: rivaroxaban may be considered a low solubility compound.

… is the end of the story.

Dif-tor heh smusma 🖖
Helmut Schütz

The quality of responses received is directly proportional to the quality of the question asked. 🚮
Science Quotes
Obinoscopy
★

USA,
2020-07-16 14:36
(758 d 12:29 ago)

@ Helmut
Posting: # 21715
Views: 2,139

## Biowaiver only for BCS I and – under certain conditions – BCS III drugs

» … is the end of the story.

He is seeking additional strength biowaiver and not BCS based biowaiver. The story might not have ended after all....there should be a sequel somewhere.

Scopy
dshah
★

India/United Kingdom,
2020-07-17 06:27
(757 d 20:38 ago)

@ Obinoscopy
Posting: # 21728
Views: 2,092

## Biowaiver only for BCS I and – under certain conditions – BCS III drugs

» » … is the end of the story.
»
» He is seeking additional strength biowaiver and not BCS based biowaiver. The story might not have ended after all....there should be a sequel somewhere.

Thank you everyone for your valuable suggestions!

Yes, I am seeking for additional strength biowaiver through in vitro dissolution testing.
Is there any alternative for media selection?
I believe 2.5X8 tab Vs 20 mg, 10X2 tab vs 20 mg and 15 vs 20 mg strength using 0.4% SDS media is one of the option, but is there any other options for dissolution comparision?

Regards,
dshah
Obinoscopy
★

USA,
2020-07-18 03:13
(756 d 23:53 ago)

@ dshah
Posting: # 21738
Views: 2,045

Hi dshah

» I believe 2.5X8 tab Vs 20 mg, 10X2 tab vs 20 mg and 15 vs 20 mg strength using 0.4% SDS media is one of the option, but is there any other options for dissolution comparision?

I am not well versed in Additional Strength Biowaivers but I think one of the basic requirements is that the dissolution media should not contain any surfactant at all.

Scopy
wienui
★

Germany/Oman,
2020-07-18 18:00
(756 d 09:05 ago)

@ dshah
Posting: # 21742
Views: 2,090

Dear dshah & All,

» I believe 2.5X8 tab Vs 20 mg, 10X2 tab vs 20 mg and 15 vs 20 mg strength using 0.4% SDS media is one of the option, but is there any other options for dissolution comparision?

Yes, I think your suggestion for the in vitro comparative dissolution testing for the other additional strength biowaivers is correct. ( take care of the sink conditions).

Beside the dissolution, the followings have to be fulfilled (EMA):

- Amount of API must be < 5% of tablet core weight in the BE strength and the biowaiver strength, 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