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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 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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• 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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• 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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• 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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