Bioequivalence and Bioavailability Forum

ElMaestro
★★★

Denmark,
2017-12-25 19:28
(2676 d 22:22 ago)

Posting: # 18081
Views: 6,495

Disturbing wording [Dissolution / BCS / IVIVC]

Hi all,

re. FDA's new biowaiver guidance Bioavailability and Bioequivalence Studies for Immediate-Release Solid Oral Dosage Forms Based on a Biopharmaceutics Classification System:

I do absolutely not like this sentence on page 8 re. the calculation of f2:
"Two dissolution profiles are considered similar when the f2 value is ≥ 50. To allow the use of mean data, the coefficient of variation should not be more than (...)"

If taken verbatim this means that an f2-based method is not acceptable when the CV is high, full stop. In that case I believe there's just the Mahalanobis distance left as a semi-bad proposal for a way forward.
I think and hope they meant something like "Two dissolution profiles are considered similar when the f2 value is ≥ 50. To allow the use of the plain f2 as a measure of similarity of dissolution profiles, the coefficient of variation should not be more than (...)"
- this would keep the door open for bootstrapping which was what was done internally at FDA for the now slightly famous Mesalamine case.

Goodbye to bootstrapping or just a little snafu when they wrote the draft?

—
Pass or fail!
ElMaestro

Helmut ★★★ Vienna, Austria, 2017-12-26 14:14 (2676 d 03:35 ago) @ ElMaestro Posting: # 18086 Views: 5,329	Disturbing wording Post reply
	Hi ElMaestro, that’s not new. Same wording was already given in the FDA’s August 2000 Guidance and the Draft Revision 1 of May 2015. Same story in Appendix I of the EMA’s BE-GL. — Dif-tor heh smusma 🖖🏼 Довге життя Україна! Helmut Schütz The quality of responses received is directly proportional to the quality of the question asked. 🚮 Science Quotes

sameep ☆ India, 2017-12-28 12:10 (2674 d 05:39 ago) @ Helmut Posting: # 18110 Views: 5,094	Literature reported Permeability Studies Accepted? Post reply
	Hi All, Are permeability studies reported in literature (like absolute bioavailability >85%) acceptable for establishing BCS class I and apply for BCS Biowaiver (ANDA)? or we have to reinvent the Universe? Regards, Sameep.

Helmut
★★★

Vienna, Austria,
2017-12-28 13:17
(2674 d 04:32 ago)

@ sameep
Posting: # 18113
Views: 5,205

Reliable source, sufficient number of subjects

Post reply

Hi Sameep,

❝ Are permeability studies reported in literature (like absolute bioavailability >85%) acceptable for establishing BCS class I and apply for BCS Biowaiver (ANDA)?

IMHO, studies from trustworthy sources (not published in the “Timbuktu Journal of Clinical Pharmacology”) should suffice. The devil is in the details. Likely those studies were performed by the originator – quite often in just twelve subjects. The guidance (Section B.1.) tells us:

A sufficient number of subjects should be enrolled to provide a reliable estimate of extent of absorption.

(my emphasis)

However, in a recent review* we find:

Permeability/Stability in the GIT
When the drug is in solution, the in vivo permeation does not depend upon the quality of the API but of the mechanism of permeation and on drug stability. For this reason, the EMA considers published human data as sufficient. The USA will consider published data only in a supportive capacity because the underlying data is not available for review, and thus, it cannot be confirmed that proper methodology was used.

Given that, for an ANDA I would say you have to re-invent the wheel. Good luck manufacturing the IV formulation according to cGMP. Ask the OGD what a “sufficient number of subjects” is.

Cardot J-M, García Arieta A, Paixão P, Taševská I, Davit B. Implementing the Biopharmaceutics Classification System in Drug Development: Reconciling Similarities, Differences, and Shared Challenges in the EMA and US-FDA-Recommended Approaches. AAPS J. 2016;18(4):1039–46. doi:10.1208/s12248-016-9915-0.

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

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

sameep ☆ India, 2018-01-02 10:35 (2669 d 07:15 ago) @ Helmut Posting: # 18132 Views: 5,129	Comparative BA study vs Biowaiver for BCS I Post reply
	Dear Helmut, ❝ Given that, for an ANDA I would say you have to re-invent the wheel. That was the first impression. Thanks for confirming. So, its better to conduct a comparative bioavailability study for BCS I, rather than biowaiver approach.

Disturbing wording [Dissolution / BCS / IVIVC]

Disturbing wording

Literature reported Permeability Studies Accepted?

Reliable source, sufficient number of subjects

Comparative BA study vs Biowaiver for BCS I