Extensions of BCS-

Based Biowaivers:

Opportunities for New

Product Classes and

a Review of the 2015

FDA Guidance

Barbara M Davit

Executive Director

Biopharmaceutics, MRL

Development of Complex Drug Products: Opportunites, Challenges, Solutions for ANDA, 505(b)(2)

9-17-2015

The following represents the personal opinions of the author and not necessarily the official position of MRL or the US-FDA

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• The role of the BCS in developing new and generic drugs

• The new draft US-FDA BCS Guidance

• Questions about implementing aspects of the US-FDA draft BCS guidance

• Summary and conclusions

Agenda

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The role of the BCS in new and generic drug development

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• The Biopharmaceutics Classification System (BCS) is an important approach for waiving the regulatory requirement for in vivo bioavailability (BA) and bioequivalence (BE) studies in both new and generic drug development

• Premises underlying the BCS

– If two drug products have the same in vivo dissolution profile under all intestinal luminal conditions, then they will have the same rate and extent of absorption

– The two key factors governing drug absorption are aqueous solubility and intestinal permeability

• Thus, the BCS is a scientific framework for classifying drug substances based on aqueous solubility and intestinal permeability

What is the BCS?

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Class 1

High solubility

High permeability

Class 2

Low solubility

High permeability

Class 3

High solubility

Low permeability

Class 4

Low solubility

Low permeability

What are the BCS classes?

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How can BCS application be pivotal to a new

or generic drug biopharmaceutics program?

• Demonstrating that two drug products are bioequivalent is an essential drug product standard for both innovator and generic drug products

New drug development

• Bridge formulations during development

• Support some types of post-approval changes

Generic drug development

• Compare rate and extent of absorption for a generic vs its reference

• Support some types of post-approval changes

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The new US-FDA draft BCS Guidance

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• Provides recommendations for sponsors of INDs, ANDAs, and supplements

– Those who wish to request a waiver of in vivo BA and/or BE studies for IR solid oral dosage forms

• Waivers are intended to apply to

– Subsequent in vivo BA or BE studies of formulations after the initial establishment of the in vivo BA of IR dosage forms during the IND period; and

– In vivo BE studies of IR dosage forms in ANDAs

• Guidance includes biowaiver extension to BCS Class 3 drug products, and additional modifications

What does the new US-FDA BCS Guidance

accomplish?

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Eligible for

biowaiver

2000 FDA BCS

Guidance

2015 Draft BCS

Guidance

Harmonized with

EMA, WHO?

Eligible for

biowaiver

IR solid oral

dosage forms

IR solid oral

dosage forms

Yes

Pharmaceutical

equivalents

Pharmaceutical

alternatives (with

justification)

Yes

IR solid oral

dosage forms only

ODTs, if provide

evidence of no

absorption from

oral cavity

Yes with EMA

Drugs with linear

PK

Drugs with linear

PK

Yes

Biowaivers not

permitted

Sublingual, buccal

IR dosage forms,

ODTs

IR Sublingual,

buccal dosage

forms

Yes

NTI drugs NTI drugs Yes

What types of drug products are eligible for

BCS biowaivers?

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BCS Class Properties Criteria Harmonized with

EMA, WHO?

• Class1

• both 2000

Guidance

and 2015

Draft

Guidance

Excipients

• Use well-established

excipients

• Advisable to use

quantitatively similar

amounts of critical

excipients

Yes

In vivo

permeability

≥ 90% for 2000 Guidance

≥ 85% for 2015 Guidance

Yes for 2015 Draft

Guidance

In vitro

dissolution

Rapid dissolution

≥ 85% in 30 minutes, all

media

Yes

• Class 3

• Proposed

in 2015

Guidance

Excipients Quantitatively the same and

qualitatively very similar Yes

In vitro

dissolution

Very rapid dissolution

≥ 85% in 15 minutes Yes

Which BCS class IR solid oral dosage forms

are elibible for biowaiver?

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How to show high solubility?

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Property 2000 FDA BCS

Guidance

2015 Draft FDA

BCS Guidance

EMA, WHO

recommend

pH range 1-7.5 1-6.8 1.2-6.8

Sampling Not specified

pH=pKa

pH=pKa +1

pH=pKa – 1

pH=1

pH=6.8

EMA: At least

1.2, 4.5, 6.8, and

at pKa if in

range

WHO: Not

specified

Volume ≤250 mL ≤250 mL ≤250 mL

Highest unit

tested Strength Strength Single dose

Type of

study

2000 FDA BCS

guidance

2015 Draft FDA BCS

Guidance EMA, WHO recommend

In vivo Absolute BA Absolute BA Absolute BA

Mass balance

• Mass balance

• If < 85% excreted

in unchanged in

urine, must

document GI

stability

• Mass balance

• EMA specifies

combined urinary and

fecal recovery of

Phase 1 and 2

oxidative metabolites

must ≥ 85% of dose

Other

methods

In vitro using a

monolayer of

epithelial cells

In vitro using a

monolayer of cultured

epithelial cells only for

passively absorbed

drugs

Supportive only

Animal models

Animal models only

for passively

absorbed drugs

Supportive only

How to show high permeability?

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Conditions 2000 FDA BCS

Guidance

2015 FDA Draft

BCS Guidance

EMA, WHO

recommend

Multi-media, pH 1, 4.5, 6.8 1, 4.5, 6.8 1.2, 4.5, 6.8

If Apparatus 1,

rotational speed 100 rpm 100 rpm 100 rpm

If Apparatus 2,

rotational speed 50 rpm 75 rpm

EMA: 50 rpm,

other speeds may

be considered with

justification

WHO: 75 rpm

Volume of media 900 mL 500 mL 900 mL

Rapidly dissolving

profile comparison f2 f2 f2

Very rapidly

dissolving profile

comparison

Not addressed (no

Class 3

biowaivers)

No need for

mathematical

calculation

No need for

mathematical

calculation

How to run in vitro dissolution studies?

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Questions about implementing the new US-FDA BCS Draft Guidance

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• Originally posted on May 6, 2015

• FDA received comments until July 6, 2015

• Comments are still welcome but those submitted before the deadline will be considered most expeditiously

• Comments will be evaluated as FDA finalizes the BCS Guidance

• Comments to the draft Guidance can be found here:

– http://www.regulations.gov/#!docketBrowser;rpp=25;po=0;dct=PS;D=FDA-2015-D-1245

• Comments were received from new and generic drug companies, and from several professional societies of pharmaceutical scientists

Information about the draft US-FDA BCS

Guidance

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• Entitled: Dissolution testing and specification criteria for immediate-release solid oral dosage forms containing BCS Class 1 and 3 drugs

• Posted: August 3, 2015

• Comments accepted until: October 3, 2015

• Submit comments to the draft guidance at: www.regulations.gov

• Electronic Federal Register notice will take the reader to the draft guidance and explain comment process

– https://www.federalregister.gov/articles/2015/08/03/2015-18968/dissolution-testing-and-specification-criteria-for-immediate-release-solid-oral-dosage-forms

A second draft US-FDA BCS Guidance was

posted in August, 2015

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Revision Comment

Media volume of 500 mL

• Please consider changing back to 900 mL

• 900 mL is standard compendial volume

for dissolution testing

• 500 mL may not represent sink conditions

• 500 mL not in harmony with other

regulatory agencies

• What data support using 500 mL?

Using mass balance studies as

evidence of high permeability

Consider harmonizing with EMA guideline:

the sum of urinary recovery of parent

compound and the urinary and fecal

recovery of oxidative drug metabolites

account for ≥85% of dose

BCS expansion

Consider expanding to Class 2 weak acids

which have dose: solubility ratio of 250 mL

or less at pH 6.8

Review of comments to the draft BCS

Guidance

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Revision Comment

Use of pH 6.8 buffer for in vitro

dissolution testing Consider FaSSIF as an alternative medium

Use of highest strength for in vitro

solubility testing

Consider harmonizing with other regulatory

agencies by testing the highest single dose

administered

Prodrug extent of absorption

• When prodrug-to-drug conversion is

shown to occur predominantly after

intestinal membrane permeation, the

extent of absorption of the prodrug should

be measured

• When this conversion occurs prior to

intestinal absorption, the extent of

absorption of the drug should be

measured

Review of comments to the draft BCS

Guidance (cont’d)

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Revision Comment

Sampling at various pH levels for

high solubility studies

• What to do for a drug that has two or

more pKa values in the “relevant pH

range”?

• Is this limited to drugs that have pKa

values between 2 and 5.8?

Recommends dissolution

sampling as early as 5 and 10

minutes

The early sampling time is unnecessary

• May reflect disintegration rather than

dissolution

• Often subject to high variability

Efflux ratio for in vitro permeability

studies should be < 2 for test

drugs, and allows no flexibility to

adjust this threshold based on

“prior experience with the cell

system used.”

• The FDA DDI guidance states that a net

flux ratio cutoff ≥ 2 is a positive signal for

further evaluation

• The language in the FDA BCS Guidance

should more closely reflect that in the

DDI Guidance, and permit revision of the

efflux ratio if appropriately justified

Review of comments to the draft BCS

Guidance (cont’d)

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Revision Comment

“Qualitatively very similar”

requirement for Class 3 excipients

Consider allowing data to be presented that

show that an excipient does not affect the

absorption of a compound

For fixed-dose combination, the

draft guidance requires that

excipients be the same between

test and reference formulations

It is unclear if this refers to the excipients of

the individual reference formulations and the

corresponding component in the FDC

Use of f2 test for dissolution

profile comparison

Can a biowaiver be enabled if all other BCS

criteria are met for a Class 1 drug except for

a failing f2 test between test and reference?

Expansion of biowaivers to

include ODT, provided there is

evidence showing no absorption

in oral cavity

• It is not clear how to rule out absorption in

the oral cavity without a separate complex

clinical study

• What other factors can be considered in

granting a BCS biowaiver for an ODT?

Review of comments to the draft BCS

Guidance (cont’d)

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Summary and conclusions

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• The BCS is well-established as an approach for waiving in vivo BA and BE studies for IR solid oral dosage forms, provided that regulatory criteria are met

• FDA posted a new draft guidance for industry facilitating BCS biowaivers of both Class 1 and Class 3 drugs; new draft guidance is well-harmonized with EMA and WHO guidelines (although still some differences)

• Comments to the draft guidance were submitted to the US regulations.gov docket, and are under review by FDA

Summary and conclusions

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• Nagesh Bandi, Pfizer

• Sid Bhoopathy, Absorption Systems

• Jean-Michel Cardot, Université d’Auvergne, France

• Jack Cook, Pfizer

• Paul Fackler, Merck

• Vivian Gray, Dissolution Technologies

• Isadore Kanfer, Rhodes University

• David Storey, Merck

• Yu Chung Tsang, Apotex

• Henry Wu, Merck

Acknowledgments

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Thank you for your attention!

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