Biowaiver Approaches for Solid Oral Dosage Forms

in New Drug Applications

Poonam R. Delvadia, Ph.D.

Division of Biopharmaceutics\ONDP\OPQ\CDER\FDA

PQRI BTC Webinar

December 06, 2018
 DISCLAIMER

The presentation reflects the views of the

presenter and should not be construed to
represent FDA’s views or policies

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 Presentation Outline
• Role of Biopharmaceutics
• In Vivo Bioavailability (BA) / Bioequivalence (BE) Assessment
• In Vitro and In Vivo Bridging for Assessment of Multiple Strengths and
Product Changes
• Biowaivers
• Biowaiver Approaches and Case Examples
– 21 CFR 320.22(d)(2) Based Approach
– Biopharmaceutics Classification System (BCS) Based Approach
– Risk Assessment for bridging drug product changes and multiple strengths
– Safe Space Approach
• Bracketing Approach
• Virtual BE
• In Vitro In Vivo Correlation (IVIVC)
• Concluding Remarks
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 Role of Biopharmaceutics

Drug Product Quality Patient

Critical
In Vivo Performance
Material/Process/
of Drug Product
Quality Attributes
(CMA, CPP, CQA) BIOPHARMACEUTICS e.g., Bioavailability
(BA)/Bioequivalence
e.g., In Vitro
(BE) data
Dissolution

Science and Risk Based Approach

Consistent
Clinically Relevant Specifications
Therapeutic Effect 4
 In Vivo BA/BE Assessment
• Bioavailability – Rate and extent of drug exposure

• Bioequivalence – Absence of significant difference in the rate

and extent of drug exposure

• These in vivo studies required as per § 21 CFR 320.21 for the

drug product approval

• Pivotal role in Drug Product’s Life-Cycle (Pre- and Post- Approval)

– To support major formulation and manufacturing changes

– To support the approval of multiple strengths

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§ 21 CFR 320.1; § 21 CFR 314.3
 Risk Level Assessment of Formulation/Manufacturing Changes

• Type of bridging needed based on the level of risk resulting

from CMC changes and impact of change on product quality
and in vivo performance
In Vivo
Product
In Vitro Bridging Bridging
Strengths
(BA/BE studies)

Minor Changes Major Changes

Unlikely to have any Likely to have a Biowaivers
detectable impact significant impact

Moderate Changes
Could have a
significant impact

FDA SUPAC IR Guidance (1995) 6

FDA SUPAC MR Guidance (1997)
 Biowaivers
• Waiver of In Vivo BA/BE Studies
– Requirements met as outlined in § 21 CFR 320.22
– Supported by in vitro tests (e.g., dissolution testing)

N=101 Biowaiver Requests

(Solid Oral Dosage Forms)
(Year 2008 - 2015)

Biowaiver is Biowaiver is
not needed Applicable 7
 Biowaiver Approaches for
Solid Oral Dosage Forms
CFR
21 CFR 320.22(d)(2)

Safe Space
BCS
Biowaiver Bracketing Approach
Approaches Virtual BE
IVIVC

Risk Assessment*

* Applicable to bridge product changes and strengths when waiver requirements are not met
21 CFR 320.22
FDA Guidance for Industry. Waiver of In Vivo BA/BE Studies for IR Solid Oral Dosage Forms Based on a Biopharmaceutics Classification System. December 2017 8
FDA Guidance for Industry – Extended Release Oral Dosage Forms : Development, Evaluation, and Application of In Vitro/In Vivo Correlations
 Biowaiver Approaches for
Solid Oral Dosage Forms

N=101 Biowaiver Requests

(Solid Oral Dosage Forms)
(Year 2008 - 2015)

Dissolution – One of the key elements in these biowaiver approaches 9

 21 CFR 320.22(d)(2) Based Biowaiver Approach

CFR
21 CFR 320.22(d)(2)

Safe Space
BCS
Biowaiver Bracketing Approach
Approaches Virtual BE
IVIVC

Risk Assessment*

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* Applicable to bridge product changes and strengths when waiver requirements are not met
 21 CFR 320.22(d)(2) Based Biowaiver

• Applicable for demonstration of product strength equivalence

• BA/BE can be demonstrated by an in vitro testing in lieu of an in vivo study for
product strengths not tested in vivo if these strengths meet all the criteria set
forth in the CFR

– In Vivo BA/BE data on the reference strength (commonly highest strength)

– Same Dosage Form
– Same Manufacturing Process
– Compositional Proportionality
– In Vitro Dissolution Similarity
– PK linearity over therapeutic dosage range
– Same drug release mechanism (MR solid oral dosage forms)
– Demonstration of the clinical need of the proposed strength (Higher strength)
– Clinical safety and/or efficacy data on the proposed dose

21 CFR 320.22 11
FDA Draft Guidance for Industry - Bioavailability and Bioequivalence Studies Submitted in NDAs or INDs — General Considerations (2014)
 Strength Dependent Dissolution

In vitro strength dependent dissolution profile is defined as the

difference in drug dissolution profiles among strengths of the
same oral drug product, i.e., there is dissolution dissimilarity
between test strength and reference strength
(e.g., similarity factor f2 < 50)

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 21 CFR 320.22(d)(2)
Case Example 1 – Strength Dependent Dissolution
• Drug Product X - Drug A
• Immediate release tablet
• Two strengths
• BCS Class 2 drug substance
– pH dependent solubility: Solubility decreases with increase in pH
• An in vivo BE study bridging lower strength (Phase 2 formulation) and
higher strength [Phase 3/to-be-marketed formulation (TBM)]
– Major Formulation Change (Phase 2 to Phase 3)
– BE demonstrated for phase 2 and phase 3 formulation
– No PK data for lower strength (TBM)

• Biowaiver request for lower strength

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Suarez-Sharp, S.; Delvadia, P.R.., et. al. Regulatory Perspectives on Strength-Dependent Dissolution Profiles and Biowaiver Approaches for Immediate Release (IR) Oral Tablets in New Drug Applications. AAPSJ.
2016. May 18(3): 578-588
 Case Example 1 – Strength Dependent Dissolution

• Multimedia dissolution comparing two strengths

– pH 1.2, pH 4.5, pH 6.8
– Dissolution similar at pH 1.2
– Dissolution not similar at pH 4.5 and 6.8 (f2 < 50)
• Dissolution dissimilarity
– Strength dependent dissolution
– Sink condition differences

pH 4.5

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 Case Example 1 – Strength Dependent Dissolution

pH 4.5
Multiunit Dissolution
f2>50

• Vertical dissolution comparison

• Multiunit dissolution similarity in
pH 4.5 and pH 6.8 supported
biowaiver pH 4.5

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 21 CFR 320.22(d)(2) Based Biowaiver - Summary

• 21 CFR 320.22(d)(2) – Dissolution similarity is a requirement

• Factors causing strength dependent dissolution

– Sink condition differences
– Formulation differences
– Manufacturing process/Quality attribute differences (e.g., Hardness)

• Other strategies to support biowaiver

– Horizontal dissolution comparison
– Indirect bioequivalence (BE) bridge
– Bracketing BE Approach

• Selection of the strategy when strength dependent dissolution is observed

– Factor causing strength dependent dissolution
– Type of in vitro/in vivo data generated as part of drug development

16
Suarez-Sharp, S.; Delvadia, P.R.., et. al. Regulatory Perspectives on Strength-Dependent Dissolution Profiles and Biowaiver Approaches for Immediate Release (IR) Oral Tablets in New Drug
Applications. AAPSJ. 2016. May 18(3): 578-588
 Biopharmaceutics Classification System
(BCS) Based Biowaiver

CFR
21 CFR 320.22(d)(2)

Safe Space
BCS
Biowaiver Bracketing Approach
Approaches Virtual BE
IVIVC

Risk Assessment*

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* Applicable to bridge product changes and strengths when waiver requirements are not met
 BCS Based Biowaiver Approach
• BCS framework – Drug substance categorized into four classes

Biowaiver application for IR solid

oral dosage forms containing BCS
class 1 and 3 drug substances

• Drug product – rapidly dissolving (≥ 85% in 30 min) or very rapidly dissolving

(≥ 85% in 15 min) in multimedia

FDA Guidance for Industry. Waiver of In Vivo BA/BE Studies for IR Solid Oral Dosage Forms Based on a Biopharmaceutics Classification System. December 2017 18
https://www.researchgate.net/figure/Biopharmaceutical-classification-system-57_fig3_11646132
 BCS Based Biowaiver Approach

Data To Support BCS Based Biowaiver Request

BCS class 1 drug products BCS class 3 drug products
Highly soluble (pH 1- 6.8)
Highly soluble (pH 1- 6.8)
Highly permeable
T and R products are rapidly dissolving T and R products are very rapidly dissolving
(≥ 85% in 30 min) (≥ 85% in 15 min)
No excipients that affect rate or extent of drug Qualitative sameness and quantitative similarity
absorption in formulation
Similarity in dissolution profiles between T and R Similarity in dissolution profiles between T and R

T – Test Product 19
R – Reference Product
 BCS Based Biowaiver
Case Example 2 – Biowaiver for Pharmaceutical Alternative

• BCS class 1 based biowaiver for pharmaceutical alternative

drug product
– Change from tablet to capsule
• Data to support
– High solubility
– High permeability
– Rapid dissolution in multimedia (>90% in 10 min)
– Excipient differences were not expected to alter BA
– Dissolution similarity between test and reference products

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 BCS Based Biowaiver – Summary
• Common deficiencies
– Insufficient number of pH conditions (as per BCS guidance) to define pH
solubility profile
– Absence of analytical validation report
– Lack of stability indicating assay
– Incomplete information on permeability studies
– Lack of data on gastrointestinal stability of drug
– Lack of dissolution information, etc.

• Complete set of data and adequate justification to support BCS

designation and biowaiver requests are necessary

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 Risk Assessment Based Biowaiver

CFR
21 CFR 320.22(d)(2)

Safe Space
BCS
Biowaiver Bracketing Approach
Approaches Virtual BE
IVIVC

Risk Assessment*

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* Applicable to bridge product changes and strengths when waiver requirements are not met
 Risk Assessment
Case Example 3 – Support Minor Manufacturing Change

• Risk Assessment to support minor change when dissolution similarity failed

• Immediate release tablet, High solubility drug substance

TBM – To-Be-Marketed; CTF – Clinical Trial Formulation 23

P R Delvadia, S S Sharp, J Z Duan, and P R Seo. Risk Based Approach for Biowaiver Application to Immediate Release (IR) Solid Oral Dosage Forms. Poster Presentation. AAPS 2016
 Risk Assessment
Case Example 3 – Support Minor Manufacturing Change

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 Risk Assessment Based Biowaiver - Summary

• Consideration of comprehensive analysis of in vitro and in

vivo information in the context of CMC changes
– Biopharmaceutics characteristics
• API and formulation characteristics
– Control strategy (CMAs, CPPs, in-process controls)
– Exposure/response relationship
– Safety profile

• Comprehensive analysis can lead to successful bridging

centered on risk-based approach

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 Safe Space Based Biowaiver

CFR
21 CFR 320.22(d)(2)

Safe Space
BCS
Biowaiver Bracketing Approach
Approaches Virtual BE
IVIVC

Risk Assessment*

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* Applicable to bridge product changes and strengths when waiver requirements are not met
 Safe Space Approaches
• Safe space – Boundaries defined by dissolution profiles within which drug
product batches are anticipated to be bioequivalent to one another

Bioequivalent

Safe Space
Outside of Safe Space
In vivo performance not known

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Sandra Suarez-Sharp, et. al. Applications of Clinically Relevant Dissolution Testing. Workshop Summary Report. The AAPS Journal (2018) 20: 93
 Safe Space Approaches
• Safe space can be defined by – Bracketing approach, virtual bioequivalence, and IVIVC
• Application for both setting clinically relevant drug product specification and gaining
regulatory flexibility i.e., biowaiver
• Safe space based on Approach B, C1, and C2 is wider than based on pivotal clinical trial
batches
• Selection of the safe space approach depends on the type of data available

IVIVC based safe space

Virtual BE based safe space

Bracketing Approach based safe space

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Sandra Suarez-Sharp, et. al. Applications of Clinically Relevant Dissolution Testing. Workshop Summary Report. The AAPS Journal (2018) 20: 93
Safe Space - Bracketing Approach

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 Bracketing Approach
• Demonstration of bioequivalence between strengths or drug product
variants representing the extremes in dissolution profiles. All dissolution
profiles falling within the BE dissolution bounds are considered to be BE.

Bioequivalent

Safe Space
Outside of Safe Space
In vivo performance not known

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 Bracketing Approach Based Safe Space
Case Example 4 – Bridging of Intermediate Strength

• Drug Product B - IR/ER Tablet (Drug X and Drug Y respectively)

• Three strengths
• Both IR and ER components contain BCS Class 3 drug substances
• Lowest and highest strength bioequivalent to the respective strength of the
reference product
• Biowaiver request for intermediate strength
• For Drug Y and for intermediate strength,
– Multimedia dissolution similar for Drug Y (f2 > 50)

• For Drug X and for intermediate strength,

– Multimedia dissolution not similar for Drug X (f2 < 50)

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 Case Example 4 – Bracketing Approach Based Safe Space

• Dissolution profile of Drug X for IS is within the dissolution bounds of LS

and HS that are bioequivalent
LS – Lowest Strength
IS – Intermediate Strength 32
HS – Highest Strength
 Bracketing Approach - Summary

• Leverage clinical BE studies conducted as part of drug

development program
– Study of different strengths
– Study of critical material attributes, critical formulation variables,
and/or critical process parameters

• Successful bracketing approach will provide a safe space

leading to regulatory flexibility

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Safe Space – Virtual Bioequivalence (BE)

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 Virtual BE Based Safe Space
• Virtual BE study using physiologically based biopharmaceutics modeling (PBBM) approach to demonstrate
bioequivalence between test and reference drug products

• PBBM uses mechanistic models which integrate physicochemical properties of API, physiological
conditions, and formulation variables (e.g., dissolution profile as a function of formulation variables) for
prediction of systemic exposure vs time

Verified Model
Test and Reference are BE
Virtual BE Study

Safe Space

Test drug product – virtual (green) dissolution profile

Reference drug product – observed (blue) dissolution profile
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 Virtual BE Based Safe Space

Safe Space

Xavier J. H. Pepin, Talia R. Flanagan et. al., Justification of Drug Product Dissolution Rate and Drug Substance Particle Size Specifications Based on Absorption PBPK 36
Modeling for Lesinurad Immediate Release Tablets. Molecular Pharmaceutics. 2016. 13, 3256 – 3269.
 Virtual BE - Summary
• Virtual BE is a valuable tool
– Gaining experience in regulatory applications e.g., setting clinically relevant drug
product specification
• However, biowaiver application is limited
– Lack of confidence on the model
• Thorough model verification to increase confidence in the model prediction
– Verification using BE and non-BE batches to evaluate predictability of the model
• The regulatory application of virtual BE based safe space will depend on
the data used to develop and verify the relationship

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Sandra Suarez-Sharp, et. al. Applications of Clinically Relevant Dissolution Testing. Workshop Summary Report. The AAPS Journal (2018) 20: 93
Safe Space – In Vitro In Vivo Correlation (IVIVC)

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 IVIVC
• “A predictive mathematical model describing relationship between an in
vitro property (e.g., dissolution time profile) and a relevant in vivo
response (concentration time profile) of a drug product”
• Goal: to predict the in vivo plasma concentration-time profile
• Application:
– To support major formulation/manufacturing changes (biowaiver)
– To support product strength equivalence (biowaiver)
– To set drug product specifications [e.g., dissolution, hardness]
• Categories of IVIVC
– Level A,
– Level B,
– Level C, IVIVC
– Multiple Level C

FDA Guidance for Industry – Extended Release Oral Dosage Forms : Development, Evaluation, and Application of In Vitro/In Vivo Correlations
Sharp, S.S. et. al. (2016). Regulatory Experience in IVIVC in New Drug Applications. The AAPS Journal.
39
http://www.pharmogo.com/training.php?act=show&id=30
 Level A IVIVC
Case Example 5 – Manufacturing site change and product strength equivalence (MR product)

• Drug Product C (Drug D + Drug E)

– Fixed Dose Combination (FDC) Extended Release Capsule (IR + ER component)
– Drug D – IR granules; Drug E – ER beads
– Two strengths

• Biowaiver Request
– Lower strength
– Manufacturing site change

• Linkage for IR component was supported by comparative in vitro dissolution

• For ER component,
– Level A IVIVC established for single entity product was applied for FDC product

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 Level A IVIVC

Treatment B

Internal Validation Treatment C

• Two stage deconvolution method

• Unit impulse response from IR formulation
• Two formulation/release rates for model development
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 Application of Level A IVIVC for FDC Product

FDC ER product Product Strength Equivalence FDC ER product

Lower strength Higher strength
Difference in IVIVC based
Cmax and AUC
Drug A 20 mg (IR component) Drug A 20 mg (IR component)
prediction (<20%)
Drug B 70 mg (ER component) Drug B 140 mg (ER component)

Successful Cross Validation

(Clinical manufacturing site) (Clinical manufacturing site)

Manufacturing Site Change Bioequivalent

Difference in IVIVC based Cmax and AUC prediction (< 20%)

Single entity product

(Commercial manufacturing site)
Drug A 20 mg (IR product)
FDC ER product
Lower and Higher strength Drug B 140 mg (ER product)
Successful Level A IVIVC

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IVIVC based Safe Space

Fastest and Slowest

Release Formulations

Safe Space

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 IVIVC – Summary
• Advantages
– Reduced regulatory burden/Gain regulatory flexibility
– Supports clinically relevant drug product specification settings
– Potential of wider drug product specifications
– Approval of meaningful design space in Quality by Design framework
• Low success rate
– Insufficient considerations of in vivo situation with conventional IVIVC
methodologies
• Physiologically based/Mechanistic IVIVC has promising advantages
to address limitation with conventional methodologies

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Sandra Suarez-Sharp, Min Li., et. al. Regulatory Experience with In Vivo In Vitro Correlations (IVIVC) in New Drug Applications. The AAPS Journal. 18 (6), Nov 2016. 1379 - 1390
 Concluding Remarks
• Approaches for Biowaiver
– Selection of approach depends on the type of in vitro and in vivo data available
– Dissolution is one of the key elements
– Establishment of in vitro – in vivo link and clinical relevance for biowaiver applications and lifecycle
management of drug products

• Establishment of safe space

– Leveraging knowledge gained from product development stages and biopharmaceutics principles help
build safe space for regulatory flexibility
– IVIVC is gold standard for gaining regulatory flexibility

• Physiologically based biopharmaceutics modeling is promising for

– Regulatory flexibility (wider specifications, biowaivers, study of the excipient effect from BCS perspective)
– Establishment of clinically relevant drug product specifications
– Understanding of the impact of CMAs/CPPs/CQAs on in vivo performance
– Lifecycle management of the drug product

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 Acknowledgements
• Sandra Suarez Sharp, Ph.D.
• Kimberly Raines, Ph.D.
• Paul Seo, Ph.D.
• Min Li, Ph.D.
• John Duan, Ph.D.
• Meng Wang, Ph.D.
• Division of Biopharmaceutics Colleagues

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