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Biowaiver Approaches for Solid Oral Dosage Formsin New Drug ApplicationsPoonam R. Delvadia, Ph.D.Division of Biopharmaceutics\ONDP\OPQ\CDER\FDAPQRI BTC WebinarDecember 06, 2018

DISCLAIMERThe presentation reflects the views of thepresenter and should not be construed torepresent FDA’s views or policies2

Presentation Outline Role of Biopharmaceutics In Vivo Bioavailability (BA) / Bioequivalence (BE) Assessment In Vitro and In Vivo Bridging for Assessment of Multiple Strengths andProduct Changes Biowaivers Biowaiver Approaches and Case Examples––––21 CFR 320.22(d)(2) Based ApproachBiopharmaceutics Classification System (BCS) Based ApproachRisk Assessment for bridging drug product changes and multiple strengthsSafe Space Approach Bracketing Approach Virtual BE In Vitro In Vivo Correlation (IVIVC) Concluding Remarks3

Role of BiopharmaceuticsDrug Product QualityCriticalMaterial/Process/Quality Attributes(CMA, CPP, CQA)PatientIn Vivo Performanceof Drug ProductBIOPHARMACEUTICSe.g., In VitroDissolutionScience and Risk Based ApproachClinically Relevant Specificationse.g., Bioavailability(BA)/Bioequivalence(BE) dataConsistentTherapeutic Effect4

In Vivo BA/BE Assessment Bioavailability – Rate and extent of drug exposure Bioequivalence – Absence of significant difference in the rateand extent of drug exposure These in vivo studies required as per § 21 CFR 320.21 for thedrug 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§ 21 CFR 320.1; § 21 CFR 314.35

Risk Level Assessment of Formulation/Manufacturing Changes Type of bridging needed based on the level of risk resultingfrom CMC changes and impact of change on product qualityand in vivo performanceIn VivoIn Vitro BridgingBridging(BA/BE studies)Minor ChangesMajor ChangesUnlikely to have anydetectable impactLikely to have asignificant impactProductStrengthsBiowaiversModerate ChangesCould have asignificant impactFDA SUPAC IR Guidance (1995)FDA SUPAC MR Guidance (1997)6

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 isnot neededBiowaiver isApplicable7

Biowaiver Approaches forSolid Oral Dosage FormsCFR21 CFR 320.22(d)(2)BCSBiowaiverApproachesSafe SpaceBracketing ApproachVirtual BEIVIVCRisk Assessment** Applicable to bridge product changes and strengths when waiver requirements are not met21 CFR 320.22FDA Guidance for Industry. Waiver of In Vivo BA/BE Studies for IR Solid Oral Dosage Forms Based on a Biopharmaceutics Classification System. December 2017FDA Guidance for Industry – Extended Release Oral Dosage Forms : Development, Evaluation, and Application of In Vitro/In Vivo Correlations8

Biowaiver Approaches forSolid Oral Dosage FormsN 101 Biowaiver Requests(Solid Oral Dosage Forms)(Year 2008 - 2015)Dissolution – One of the key elements in these biowaiver approaches9

21 CFR 320.22(d)(2) Based Biowaiver ApproachCFR21 CFR 320.22(d)(2)BCSBiowaiverApproachesSafe SpaceBracketing ApproachVirtual BEIVIVCRisk Assessment*10* 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 forproduct strengths not tested in vivo if these strengths meet all the criteria setforth in the CFR–––––––––In Vivo BA/BE data on the reference strength (commonly highest strength)Same Dosage FormSame Manufacturing ProcessCompositional ProportionalityIn Vitro Dissolution SimilarityPK linearity over therapeutic dosage rangeSame 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 dose21 CFR 320.22FDA Draft Guidance for Industry - Bioavailability and Bioequivalence Studies Submitted in NDAs or INDs — General Considerations (2014)11

Strength Dependent DissolutionIn vitro strength dependent dissolution profile is defined as thedifference in drug dissolution profiles among strengths of thesame oral drug product, i.e., there is dissolution dissimilaritybetween test strength and reference strength(e.g., similarity factor f2 50)12

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) andhigher 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 strength13Suarez-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 differencespH 4.514

Case Example 1 – Strength Dependent DissolutionpH 4.5 Vertical dissolution comparisonMultiunit dissolution similarity inpH 4.5 and pH 6.8 supportedbiowaiverMultiunit Dissolutionf2 50pH 4.515

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 development16Suarez-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 DrugApplications. AAPSJ. 2016. May 18(3): 578-588

Biopharmaceutics Classification System(BCS) Based BiowaiverCFR21 CFR 320.22(d)(2)BCSBiowaiverApproachesSafe SpaceBracketing ApproachVirtual BEIVIVCRisk Assessment*17* Applicable to bridge product changes and strengths when waiver requirements are not met

BCS Based Biowaiver Approach BCS framework – Drug substance categorized into four classesBiowaiver application for IR solidoral dosage forms containing BCSclass 1 and 3 drug substances Drug product – rapidly dissolving ( 85% in 30 min) or very rapidly dissolving( 85% in 15 min) in multimediaFDA Guidance for Industry. Waiver of In Vivo BA/BE Studies for IR Solid Oral Dosage Forms Based on a Biopharmaceutics Classification System. December eutical-classification-system-57 fig3 1164613218

BCS Based Biowaiver ApproachData To Support BCS Based Biowaiver RequestBCS class 1 drug productsHighly soluble (pH 1- 6.8)Highly permeableBCS class 3 drug productsHighly soluble (pH 1- 6.8)T and R products are rapidly dissolving( 85% in 30 min)T and R products are very rapidly dissolving( 85% in 15 min)No excipients that affect rate or extent of drugabsorptionQualitative sameness and quantitative similarityin formulationSimilarity in dissolution profiles between T and R Similarity in dissolution profiles between T and RT – Test ProductR – Reference Product19

BCS Based BiowaiverCase Example 2 – Biowaiver for Pharmaceutical Alternative BCS class 1 based biowaiver for pharmaceutical alternativedrug 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 products20

BCS Based Biowaiver – Summary Common deficiencies– Insufficient number of pH conditions (as per BCS guidance) to define pHsolubility 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 BCSdesignation and biowaiver requests are necessary21

Risk Assessment Based BiowaiverCFR21 CFR 320.22(d)(2)BCSBiowaiverApproachesSafe SpaceBracketing ApproachVirtual BEIVIVCRisk Assessment*22* Applicable to bridge product changes and strengths when waiver requirements are not met

Risk AssessmentCase Example 3 – Support Minor Manufacturing Change Risk Assessment to support minor change when dissolution similarity failed Immediate release tablet, High solubility drug substanceTBM – To-Be-Marketed; CTF – Clinical Trial FormulationP 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 201623

Risk AssessmentCase Example 3 – Support Minor Manufacturing Change24

Risk Assessment Based Biowaiver - Summary Consideration of comprehensive analysis of in vitro and invivo 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 bridgingcentered on risk-based approach25

Safe Space Based BiowaiverCFR21 CFR 320.22(d)(2)BCSBiowaiverApproachesSafe SpaceBracketing ApproachVirtual BEIVIVCRisk Assessment*26* 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 drugproduct batches are anticipated to be bioequivalent to one anotherBioequivalentSafe SpaceOutside of Safe SpaceIn vivo performance not known27Sandra 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 IVIVCApplication for both setting clinically relevant drug product specification and gainingregulatory flexibility i.e., biowaiverSafe space based on Approach B, C1, and C2 is wider than based on pivotal clinical trialbatchesSelection of the safe space approach depends on the type of data availableIVIVC based safe spaceVirtual BE based safe spaceBracketing Approach based safe space28Sandra Suarez-Sharp, et. al. Applications of Clinically Relevant Dissolution Testing. Workshop Summary Report. The AAPS Journal (2018) 20: 93

Safe Space - Bracketing Approach29

Bracketing Approach Demonstration of bioequivalence between strengths or drug productvariants representing the extremes in dissolution profiles. All dissolutionprofiles falling within the BE dissolution bounds are considered to be BE.BioequivalentSafe SpaceOutside of Safe SpaceIn vivo performance not known30