Biowaiver Approaches for Solid Oral Dosage Forms in New Drug Applications Poonam R. Delvadia, Ph.D. Division of Biopharmaceutics\ONDP\OPQ\CDER\FDA

Transcription

1 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

2 DISCLAIMER The presentation reflects the views of the presenter and should not be construed to represent FDA s views or policies 2

3 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 (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 3

4 Role of Biopharmaceutics Drug Product Quality Patient Critical Material/Process/ Quality Attributes (CMA, CPP, CQA) e.g., In Vitro Dissolution BIOPHARMACEUTICS In Vivo Performance of Drug Product e.g., Bioavailability (BA)/Bioequivalence (BE) data Science and Risk Based Approach Clinically Relevant Specifications Consistent Therapeutic Effect 4

5 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 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 21 CFR 320.1; 21 CFR

6 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 Vitro Bridging In Vivo Bridging (BA/BE studies) Product Strengths Minor Changes Unlikely to have any detectable impact Major Changes Likely to have a significant impact Biowaivers Moderate Changes Could have a significant impact FDA SUPAC IR Guidance (1995) FDA SUPAC MR Guidance (1997) 6

7 Biowaivers Waiver of In Vivo BA/BE Studies Requirements met as outlined in 21 CFR Supported by in vitro tests (e.g., dissolution testing) N=101 Biowaiver Requests (Solid Oral Dosage Forms) (Year ) Biowaiver is not needed Biowaiver is Applicable 7

8 Biowaiver Approaches for Solid Oral Dosage Forms CFR 21 CFR (d)(2) BCS Biowaiver Approaches Safe Space Bracketing Approach Virtual BE IVIVC Risk Assessment* * Applicable to bridge product changes and strengths when waiver requirements are not met 21 CFR 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 FDA Guidance for Industry Extended Release Oral Dosage Forms : Development, Evaluation, and Application of In Vitro/In Vivo Correlations 8

9 Biowaiver Approaches for Solid Oral Dosage Forms N=101 Biowaiver Requests (Solid Oral Dosage Forms) (Year ) Dissolution One of the key elements in these biowaiver approaches 9

10 21 CFR (d)(2) Based Biowaiver Approach CFR 21 CFR (d)(2) BCS Biowaiver Approaches Safe Space Bracketing Approach Virtual BE IVIVC Risk Assessment* * Applicable to bridge product changes and strengths when waiver requirements are not met 10

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 FDA Draft Guidance for Industry - Bioavailability and Bioequivalence Studies Submitted in NDAs or INDs General Considerations (2014) 11

12 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) 12

13 21 CFR (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 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 May 18(3):

14 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

15 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

16 21 CFR (d)(2) Based Biowaiver - Summary 21 CFR (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 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 May 18(3):

17 Biopharmaceutics Classification System (BCS) Based Biowaiver CFR 21 CFR (d)(2) BCS Biowaiver Approaches Safe Space Bracketing Approach Virtual BE IVIVC Risk Assessment* * Applicable to bridge product changes and strengths when waiver requirements are not met 17

18 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

19 BCS Based Biowaiver Approach Data To Support BCS Based Biowaiver Request BCS class 1 drug products Highly soluble (ph 1-6.8) Highly permeable T and R products are rapidly dissolving ( 85% in 30 min) No excipients that affect rate or extent of drug absorption Similarity in dissolution profiles between T and R BCS class 3 drug products Highly soluble (ph 1-6.8) T and R products are very rapidly dissolving ( 85% in 15 min) Qualitative sameness and quantitative similarity in formulation Similarity in dissolution profiles between T and R T Test Product R Reference Product 19

20 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 20

21 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 21

22 Risk Assessment Based Biowaiver CFR 21 CFR (d)(2) BCS Biowaiver Approaches Safe Space Bracketing Approach Virtual BE IVIVC Risk Assessment* * Applicable to bridge product changes and strengths when waiver requirements are not met 22

23 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 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

24 Risk Assessment Case Example 3 Support Minor Manufacturing Change 24

25 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 25

26 Safe Space Based Biowaiver CFR 21 CFR (d)(2) BCS Biowaiver Approaches Safe Space Bracketing Approach Virtual BE IVIVC Risk Assessment* * Applicable to bridge product changes and strengths when waiver requirements are not met 26

27 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 Sandra Suarez-Sharp, et. al. Applications of Clinically Relevant Dissolution Testing. Workshop Summary Report. The AAPS Journal (2018) 20: 93 27

28 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 Sandra Suarez-Sharp, et. al. Applications of Clinically Relevant Dissolution Testing. Workshop Summary Report. The AAPS Journal (2018) 20: 93 28

29 Safe Space - Bracketing Approach 29

30 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 30

31 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) 31

32 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 HS Highest Strength 32

33 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 33

34 Safe Space Virtual Bioequivalence (BE) 34

35 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 Virtual BE Study Test and Reference are BE Safe Space Test drug product virtual (green) dissolution profile Reference drug product observed (blue) dissolution profile 35

36 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 Modeling for Lesinurad Immediate Release Tablets. Molecular Pharmaceutics ,

37 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 Sandra Suarez-Sharp, et. al. Applications of Clinically Relevant Dissolution Testing. Workshop Summary Report. The AAPS Journal (2018) 20: 93 37

38 Safe Space In Vitro In Vivo Correlation (IVIVC) 38

39 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, Multiple Level C IVIVC 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

40 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 40

41 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 41

42 Application of Level A IVIVC for FDC Product FDC ER product Lower strength Drug A 20 mg (IR component) Drug B 70 mg (ER component) (Clinical manufacturing site) (Commercial manufacturing site) FDC ER product Lower and Higher strength Product Strength Equivalence Difference in IVIVC based C max and AUC prediction (<20%) Manufacturing Site Change Difference in IVIVC based C max and AUC prediction (< 20%) FDC ER product Higher strength Drug A 20 mg (IR component) Drug B 140 mg (ER component) (Clinical manufacturing site) Bioequivalent Single entity product Drug A 20 mg (IR product) Drug B 140 mg (ER product) Successful Level A IVIVC Successful Cross Validation 42

43 IVIVC based Safe Space Fastest and Slowest Release Formulations Safe Space 43

44 Advantages IVIVC Summary 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 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

45 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 45

46 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 46

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