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  1. 1. Fundamental Considerations in theDevelopment of BiorelevantDissolution Test and Essentials ofIVIVC in Drug Development1-Day Intensive ProgramUmesh V. Banakar, PhDProfessor & PresidentBanakar Consulting ServicesCarmel, IN 46032 USAPresented toNovartis (India) Ltd.Hyderabad, INDIASponsored bySotax (India) LtdMumbai, INDIAAugust 28, 2012
  2. 2. Fundamental Considerations in the Development of Biorelevant Dissolution Test and Essentials ofIVIVC in Drug DevelopmentPrefaceThe in vitro dissolution test has emerged as the single most crucial test that has the potential to predict invivo availability. While dissolution testing is a regular quality control procedure, it plays a criticalrole during all phases of drug (formulation) development. Thus, the dissolution test can be employedprospectively – while developing a formulation with the appropriate drug release characteristics, andretrospectively – to assess whether a dosage form is releasing the drug at prescribed/predeterminedrate and extent from batch-to-batch. The principal assumption underlying these two applications ofthis test is that the dissolution test is able to adequately represent, if not predict, the biologicalperformance, i.e., bioavailability, of the drug.There is a need to understand what it takes to develop a ‘Biorelevant Dissolution Test’ method which canaccomplish the abovementioned attributes. Issues concerning the dissolution process, the dissolutiontest methodology, factors that influence dissolution process and thereby the dissolution performance,criteria for selection of a dissolution test method, ways to compute and interpret dissolution data,methods to determine and interpret IVIVC, are but a few of the many factors that need to becomprehensively evaluated during the development of a dissolution test. Consequently, thedissolution test method development is often challenging to the professionals working in drugproduct development.As of date, in vitro dissolution tests seem to be the most reliable predictors of in vivo availability. Althoughofficial tests have great practical value, the fact that there is still a need for a test more directlyrelated to bioavailability has been recognized. While the bioavailability of drug substances and drugproducts in humans can provide a confirmatory evidence of a potential relationship betweendissolution and physiological availability, it is often impractical to perform extensive and expensivehuman testing. As a result, the essentials of what is involved in developing and demonstrating an invitro - in vivo correlation is necessary.The presentation will focus on fundamental considerations in the development of Biorelevant DissolutionTest and understanding the essentials of IVIVC in drug product development.The author (UVB) wishes to acknowledge with gratitude Millennium Pharmaceuticals Inc., Cambridge,MA 02139 for sponsoring this program. UVB is indebted to his wife Suneeta for her continuousunselfish support. Last, but not the least, UVB would like to thank all the well wishers for theirsupport that is often taken for granted, however, needs to be recognized.Umesh V. Banakar, Ph.D., Professor and President, Banakar Consulting Services, Carmel, IN 46032[umeshbanakar@juno.com]
  3. 3. Fundamental Considerations in the Development ofBiorelevant Dissolution Test and Essentials of IVIVC in Drug DevelopmentUmesh Banakar, PhD, Professor and President, Banakar Consulting Services,Carmel, IN 46032 USATable of ContentsI. Introduction, Objectives and ScopeII. Biorelevant Dissolution Test Method DevelopmentPart 1: BCS ConsiderationsIII. Biorelevant Dissolution Test Method DevelopmentPart 2: Compendial versus NoncompendialIV. Biorelevant Dissolution Test Method DevelopmentPart 3: IR Solid Dosage FormsV. Biorelevant Dissolution Test Method DevelopmentPart 4: MR Solid Dosage FormsVI. Biorelevant Dissolution Test Method DevelopmentPart 5: Regulatory ConsiderationsVII. In Vitro - In Vivo CorrelationsPart 1: Basics of CorrelationVIII. In Vitro - In Vivo CorrelationsPart 2: Difficulties in Correlating Dissolution and BioavailabilityIX. In Vitro - In Vivo CorrelationsPart 3: Regulatory PerspectiveX. In Vitro - In Vivo CorrelationsPart 4: Data Analyses - in vitro and in vivoXI. In Vitro - In Vivo CorrelationsPart 5: Setting-up IVIVCXII. In Vitro - In Vivo CorrelationsPart 6: Applications and PerspectivesXIII. Concluding RemarksQ &A
  4. 4. Module I• Introduction• Objective and ScopeUmesh V. Banakar, PhD
  5. 5. Pharmaceutical Systems (Types)– Physical property based• Disintegration• Non-disintegrating– Functional property based (regulatorybased)• Immediate release• Modified release– Enteric coated– Others (PR/SR/CR/DR/ER/…)– Carrier system based• Solid (dissolution testing required)• Semi-solid (dissolution testing required)• Liquids (dissolution testing requiredexcept for true solutionsBCS-UVB
  6. 6. A K1 B K2 CIVIVC?A: Drug in dosage formB: Drug dissolved in the gutC: Drug in blood/systemic circulationD: Drug dissolved in in vitro dissolutionsystemK1: in vivo dissolution rate constantK2: in vivo drug absorption rate constantK3: in vitro dissolution rate constantUVBCorrelationK3D
  7. 7. Objectives and Scope•Fundamentals of Dissolution Testing•Biorelevant Dissolution•Discriminative Biorelevant Dissolution Testing•Basics of IVIVC•Can dissolution be correlated to bioavailability•Essentials in Setting up IVIVC• Beyond Traditional IVIVC (time permitting)Outside the scope ……•Drug specific method development•USP Dissolution Methods - instrumentation•Mechanics/mathematics of IVIVC•Interpretation and Drug Specific IVIVCUVB
  8. 8. Module IIBiorelevant Dissolution TestMethod DevelopmentPart 1: BCS ConsiderationsUmesh V. Banakar, PhD
  9. 9. • Revisiting BCS• Designing Intrinsic Dissolution Test• Interpretation of Resultsand Drawing Inferences• Connecting Intrinsic andApparent Dissolution TestUVB
  10. 10. • BiopharmaceuticsClassification System (BCS)– IR• Based on Drug Solubility andPermeability– Case 1: High Solubility – High Permeability– Case 2: Low Solubility – High Permeability– Case 3: High Solubility – Low Permeability– Case 4: Low Solubility – Low Permeability
  11. 11. • Requirements– What is the rate limiting step invivo?– Can this step be measured in vitro?
  12. 12. Designing Intrinsic DissolutionTest•Agitation Intensity•pH of dissolution medium•Sink volume•Particle size•Solubility class•Target dosage form•Others
  13. 13. Intrinsic Dissolution TestInterpretation of results anddrawing conclusions:•Agitation Intensity In/Dependency•pH In/Dependency•Sink volume – Dose size•Particle size impact•Solubility class•Target dosage form•Magnitude of Kin•OthersUVB
  14. 14. Intrinsic and ApparentDissolution Test Relationship•Agitation IntensityIn/Dependency•pH In/Dependency•Sink volume – Dose size•Particle size impact•Solubility class•Target dosage form•Magnitude of Kin•OthersUVB
  15. 15. Module IIIBiorelevant Dissolution TestMethod DevelopmentPart 2: Compendial versusNoncompendialUmesh V. Banakar, PhD
  16. 16. • Current USPXXV• Dissolution<711>– Apparatus 1– Apparatus 2Dissolution <711>– Apparatus 1– Apparatus 2– Apparatus 3– Apparatus 4– Apparatus 5– Apparatus 6– Apparatus 7UVB
  17. 17. Bioavailability Parameters andDissolution• Absorption• Distribution• Metabolism• Elimination / excretion• Dissolution rate constant (in vitro / in vivo)• Total amount dissolved (in vitro / in vivo)• Which one is dissolutiondependent?UVB
  18. 18. BIORELEVANCE OF DISOLUTIONTEST• Solubility of drug• Partitioning of drug (logP)• Type of formulation• Site of drug administration• Potential of drug release/dissolution• Is dissolution rate-limitedabsorptionUVB
  19. 19. BIORELEVANCE OF DISOLUTIONTEST -2• Potential site of drug absorption• In vivo site where dissolutioncriteria are met• In vivo where most likely IVIVC isobserved• Chemistry of the drug• Physicochemical properties of thedrug• Intrinsic dissolution considerationUVB
  20. 20. PHARMACEUTICAL SYSTEMSAND DISSOLUTION TESTCONDITIONS• Immediate Releaseformulations• Modified Release formulations• Disintegrating/Non-disintegrating systems• Solid, Semi-solid and Liquidformulations• Dose strength andDrug:Excipient RatioUVB
  21. 21. PHARMACEUTICAL SYSTEMSAND DISSOLUTION TESTCONDITIONS - 2• Drug solubility and sink conditions• Influence and importance ofhydrodynamics• pH profiling: Necessary orotherwise• Physiological considerations• Active metabolite considerationsUVB
  22. 22. PHARMACEUTICAL SYSTEMSAND DISSOLUTION TESTCONDITIONS - 3• In vivo dissolution siteconsiderations• Absorption site considerations• BA under fasted and fed states• Simulation of dissolution under fedstate• In vivo BA, f value, for the drugUVB
  23. 23. COMPENDIAL DISSOLUTIONTESTSAND BIORELEVANCE• Disintegration and Dissolution tests• Dissolution test Assembly(ies)• Compendial dissolution media• Use of solubility modifiers(surfactants, etc.)• Compendial dissolution testmedium volumeUVB
  24. 24. COMPENDIAL DISSOLUTIONTESTSAND BIORELEVANCE - 2• Hydrodrynamics in compendialmethods• pH profiling or otherwise• Acceptance criteria• Q versus Rate parameterQuality Control Tests !!!!UVB
  25. 25. NONCOMPENDIAL DISSOLUTIONTESTSAND BIORELEVANCE• Modifications in Test Assembly(ies)• Combination of compendialmethods• Hydrodynamics modifiers• Nontraditional dissolution media• Solubility modifiers (noncompendial!)• Intrinsic dissolution testUVB
  26. 26. Development ofSuitable DissolutionMethod– Europe: no monographs onformulations or individualmethods necessary– Critical criteria• Properties of dosage form– Geometry: mono or multi-particulate– Technology: conventional ormodified• Properties of drug substance– Solubility– Wettability– Stability– Others
  27. 27. Dissolution MethodDevelopment– Intrinsic dissolution• Determination of intrinsicdissolution rate constant• Low and high K intrinsic• Implications and projections– Physical and chemicalparameters• Drug substance / activeingredient• Drug substance + excipientcombination• [D + excipient] and process• Dosage form / drug carriersystem– Solubility– Crystal structure– Other
  28. 28. Development of a BiorelevantDissolution Test (General Scheme)– Determine BCS of the drug and thedosage form– Choice of appropriate test apparatus– Choice of appropriate medium for thetest– Dissolution test medium and itscharacteristics (dissolved gases,nontraditional pHs, enzymes, etc.)– Hydrodynamics (available andoptimized) of medium– Duration of the dissolution test withregard to formulation type and drugproperties– Setting criteria for evaluation of thetest results
  29. 29. Development of a BiorelevantDissolution Test (SecondaryConsiderations)– Relation between intrinsic andapparent dissolution tests– Stage of drug development– Prospective, or retrospective,test development– Test for NDA and / or ANDAproduct– Test for IR or MR product– Monograph available orotherwise (generics)
  30. 30. Development of a BiorelevantDissolution Test– Choice of appropriate testapparatus• Compendial versus noncompendial• Compendial with modification(s)• Can the essential considerations beaccommodated?• Drug substance and dosage formrequirements
  31. 31. Development of a BiorelevantDissolution Test– Choice of appropriate mediumfor the test– Dissolution test medium and itscharacteristics (dissolved gases,nontraditional pHs, enzymes,etc.)
  32. 32. Development of a BiorelevantDissolution Test– Different media suggested /available• Buffers at pHs: 1.2, 4.5, 6.8, 7.5• Buffers with or without enzymes• Simulated gastric fluid surfactant• Simulated intestinal fluid• Fasted simulated small intestinal fluid• Fed simulated small intestinal fluid• Ensure plus, milk (fat grades)• Co-solvent systems (solubizers)• Organic solvents• Aerated / deaerated media– Deaeration methods, age, etc.• Others
  33. 33. Development of a BiorelevantDissolution Test– Important considerations• Stage of drug development• Volume of dissolution medium• Duration of the test• Type of formulation and formulationexcipients• Planarity and turbulence resultantto mixing• Is discrimination or sensitivity theevaluation criterion?
  34. 34. Development of a BiorelevantDissolution Test– Duration of the dissolution testwith regard to formulation typeand drug properties• Type of dosage form: IR or MR• Rapidly dissolving or otherwise• BCS and type of dosage form /drug properties• Sampling protocol• Regions of the profile• Duration of the test and stability ofthe drug / product
  35. 35. Development of a BiorelevantDissolution Test– Setting criteria for evaluation ofthe test results• Comparative tests• Comparative test results• Establishing in vitro equivalence• Stage of drug development• Pre-biostudies or post-biostudies• Method transfer post IVIVC to QC
  36. 36. Module IVBiorelevant Dissolution TestMethod DevelopmentPart 3: IR Solid DosageFormsUmesh V. Banakar, PhD
  37. 37. • Strategy development for design• In vitro evaluation of formulations• Biorelevant dissolution test(s) anddemonstrating discrimination• Selection of Formulation from prototypeto pivotal• Beyond F1/F2 analysis• Potential prediction of in vivo availabilityand Bioequivalence• Definitive BE studies
  38. 38. Designing an Immediate ReleaseGeneric Pharmaceutical API matters most (generally) Route of synthesis – Polymorph(s) Formulation composition/component Others
  39. 39. Critical physicochemical properties ofAPI (s) Crystalinity Particle size and distribution Polymorph(s) considerations Solubility profile – pH and organic solvents Analytical considerations Impurity profile Compatibility with excipient(s) Stability profile (including tracking ofimpurities)UVB
  40. 40. Immediate Release PharmaceuticalBiopharmaceutical considerationsIn vitro Dissolution considerations Compendial/monograph requirements Define dissolution test protocol Biorelevant condition(s) Sampling protocol (honoring monograph reqmts.) Rate assessment should be feasible Set discriminatory criteria Define Acceptance CriteriaIn vitro Equivalence Assessment F1 and F2 Analyses (all testing conditions) Rate comparisons Extent comparisons In-process formulation and dosage form testingUVB
  41. 41. Case Study 1• Poorly soluble drug• No metabolism• Low dose• Short Tmax• Long terminal elimination half-life
  42. 42. Case Study 2• Poorly soluble• Relatively low dose• Low BA• Not so short Tmax• Long half-life• Active metabolite
  43. 43. Module VBiorelevant Dissolution TestMethod DevelopmentPart 4: MR Solid DosageFormsUmesh V. Banakar, PhD
  44. 44. • Defining Rate-limiting component• In vitro evaluation of formulations• Biorelevant dissolution test(s) anddemonstrating discrimination• Beyond F1/F2 analysis• Potential prediction of in vivo availabilityUVB
  45. 45. Designing Dissolution Method:Modified Release Pharmaceuticals API matters less (generally) Formulation composition/component Processing/Technology OthersUVB
  46. 46. Designing Dissolution MethodModified Release PharmaceuticalCritical physicochemical properties ofAPI (s) Crystalinity, Particle size and distribution Polymorph(s) considerations Solubility profile – pH and organic solvents Analytical considerations Impurity profile Compatibility with excipient(s) Stability profile (including tracking ofimpurities) Selection of excipients (rationale and function)UVB
  47. 47. Designing Dissolution MethodModified Release PharmaceuticalIn vitro Dissolution considerations Compendial/monograph requirements Define dissolution test protocol Biorelevant condition(s) Technology driven Noncompendialmodifications !! Sampling protocol (long duration +Clinical endpoint considns.) Rate assessment of paramountimportance Set discriminatory criteria Define Acceptance CriteriaUVB
  48. 48. Designing Dissolution MethodModified Release Pharmaceutical (contd.)In vitro In/Equivalence Assessment F1/F2 Analyses (all testing conditions) Rate comparisons Extent comparisons In-process formulation and dosage formtestingUVB
  49. 49. Case Study 1• Low dose• Poor solubility• OD• Medium Tmax• Short half-life• No metabolite
  50. 50. Case Study 2• Low dose• Poor solubility• OD• Medium Tmax• Short half-life• Active metabolite
  51. 51. Notes ……
  52. 52. Notes ……
  53. 53. Case Study 3• FDC• Low dose + high dose• Poor + high solubility• OD• Significantly different Tmaxs [2]• Significantly different half-lifes[2]• No metabolite
  54. 54. Notes ……
  55. 55. Module VIBiorelevant Dissolution TestMethod DevelopmentPart 5: RegulatoryExpectationsUmesh V. Banakar, PhD
  56. 56. Regulatory Assessmentof Oral SR/CR ProductsBiorelevant dissolutionassessment (justification) In relation to technology used In relation to the manufacturing process In relation to predicting BA and thereby BE In relation to therapeutic endpoint DEMONSTRATING DISCRIMINATION In relation to „future‟ QC specs others
  57. 57. Regulatory Assessmentof Oral SR/CR ProductsIn vitro equivalence Rate controlling step(s) Biorelevant or otherwise In relation to Monograph requirements (ifapplicable) Potential for predicting in vivo performance Beyond f1 and f2 analyses Release rate analyses Simulation, prediction and Goodness of Fit Others
  58. 58. Regulatory Assessmentof Oral SR/CR ProductsSetting dissolution/drug releasespecifications (QC) IVIVC based Non-IVIVC based Technology (employed) specific FDA Guidance based Clinical endpoint based OthersJustification is mandatorythrough discriminatory analyses
  59. 59. Module VIIIn Vitro - In Vivo CorrelationsPart 1: Basics of Correlation
  60. 60. • The process of developing adrug from discovery to themarket is long, arduous andchallenging, to say the least.• Along the way, one oftencomes across crossroads withrespect to arriving at areasonable balance betweenrisks and benefits goingbeyond achieving clinicaltargets.UVB
  61. 61. There is a constant quest forincreasing efficiency and costeffectiveness in the drugdevelopment process.In this pursuit, a question oftensurfaces relating to exploringavenues where in vitrosurrogate experiments canbe developed and used topredict in vivo outcomes.UVB
  62. 62. Such surrogate tests could impactvarious stages of drug developmentincluding setting of qualityspecifications of the finalproduct, provided an appropriatein vivo – in vitro correlation[IVIVC] can be established.The place and significance of suchIVIVCs is most encountered duringthe assessment of a drug productunder development to potentiallypredict its bioefficacy and possiblyits ultimate therapeutic efficacy,among others.UVB
  63. 63. “………Establishment of arational relationship between abiological property produced bya dosage form, and aphysicochemical property orcharacteristic of the samedosage form……..Therelationship between the twoproperties, biological andphysicochemical, is thenexpressed quantitatively.”US-FDA guideline/USP<1088>
  64. 64. • Correlation is defined as anattempt to explore arelationship between twovariables.• Variable may be defined as aprocess comprising of aninput (cause) function and theresultant output (effect).UVB
  65. 65. • Examples:Dissolution (input) AmountDissolved(effect)* Characterized as amount of drugdissolved as a function of time• Dissolution (in vivo) Amount inblood (output)* Characterized as plasma-drug-concentration as a function of timeAging (cause) Color of hair!!(effect)UVB(Process)(Process)(Process)
  66. 66. Correlation– In vitro – In vivo• Physicochemical property– Dissolution• Biological property– Pharmacokinetics– Dependent on systemUVB
  67. 67. • Requirements of a Correlation(1)– Dependent and independentvariables have to becorrelatable.– There has to be at least onedistinct common factor orsimilarity between twovariables. Otherwise, one iscorrelating apples withoranges!– Similarity in the processcomponent within twovariables is exploredUVB
  68. 68. Requirements of a Correlation (2)IVIVC in Drug DevelopmentThe significance of an IVIVC indrug development is establishedfrom:• Coefficient of correlation: r• Coefficient of determination: r2• Coefficient of dependability• Probability factor: p value• Relevance of correlationUVB
  69. 69. • Types of Correlations– Linear (positive and negative)– Exponential (positive andnegative)– Polynomial (positive andnegative)– Probability / Probit– Others• For simplicity, linear correlationis preferred.UVB
  70. 70. • Parameters of a LinearCorrelation• Slope Δ y / Δ x• Intercept: y value when x = 0• Interpretation of CorrelationMeaning of a slope:Provides insight into the function representedon the X-axisMeaning of intercept:Provides information about the dependentvariable when X is functionally non-existent ornot requiredUVB
  71. 71. Interpretation of aCorrelation (Part 2)In addition to the items listedin Part 1Statistically soundShould provide an insight intothe processes that arecorrelated or representedUVB
  72. 72. Module VIIIIn Vitro - In Vivo CorrelationsPart 2: Difficulties in CorrelatingDissolution and Bioavailability
  73. 73. A K1 B K2 CIVIVC?A: Drug in dosage formB: Drug dissolved in the gutC: Drug in blood/systemic circulationD: Drug dissolved in in vitro dissolutionsystemK1: in vivo dissolution rate constantK2: in vivo drug absorption rate constantK3: in vitro dissolution rate constantUVBCorrelationK3D
  74. 74. Mechanics of IVIVC:ChallengesIn vivo vs in vitro system inherentdifferences2-step vs 1-step ….Duration of test ….Functionality of test (1st order vsarithmatic) ….Dissolution dependent function –characterization ?What to correlate: function, response,parameter ..The issue of metabolite vs administereddrug ….Regulatory vs realistic correlation !!Mathematical vs clinical …………What is the ultimate objective of IVIVC ??UVB
  75. 75. In vivo vs in vitro systeminherent differences….12-step vs 1-step ….Dissolution in vivo is a prerequisite forBioavailability, and not the reverseWhen in vivo dissolution is the rate-limiting, then chances for predictingbioavailability (IVIVC) are enhancedUVB
  76. 76. In vivo vs in vitro systeminherent differences ….2Duration of test ….In vitro dissolution test:IR products – 0.5 h – 2 hMR products – 3 h – 30 hBioavailability test: 5 x elimn. Half-life(t1/2)___________________Fluoxetene 20 mg Capsules (Prozaic)Dissolution Test Duration: 120 min [2 h]Bioavailability Duration: 5 x 80 h = 400 hUVB
  77. 77. In vivo vs in vitro systeminherent differences ….3Functionality of test (1st order vsarithmatic)Dissolution/Drug Release function: Arithmetic Yas f(X)Bioavailability function: First Order – ln(Y) as f(X)[Exponential]Factors influencing bioavailoability have long time toexpress ….Discriminatory - Bio-relevant dissolution test isrequired –drug-specificproduct-specificUVB
  78. 78. In vivo vs in vitro systeminherent differences ….4Dissolution (in vivo) dependent functionin bioavailability process and itscharacterization ?Absorption is dissolution dependent,however, for establishing IVIVC entirebioavailability performance has to beused (including distribution, andelimination)Dissolution test presumes that postdissolution/release of the drugcomplete and rapid/instantaneousabsorption occursUVB
  79. 79. In vivo vs in vitro systeminherent differences ….5What to correlate:function, response, parameter ..Complete in vivo performance(bioavailability) and completein vitro performance (dissolution)has to be correlatedUVB
  80. 80. In vivo vs in vitro systeminherent differences ….6The issue of active metabolite vsadministered drug ….Dissolution Test: Administered drug (parentdrug)Bioavailability Test: Active metabolite__________________Naltrexone and 6-beta-naltrexol) – activemetaboliteDissolution Test: Naltrexone from tabletBioavailability Test: Plasma-6-beta-naltrexol-concn.UVB
  81. 81. In vivo vs in vitro systeminherent differences ….7Regulatory vs realistic correlation!!UVB
  82. 82. In vivo vs in vitro systeminherent differences ….8Mathematical vs clinical …………[Semi]quantitative based correlationsbetween bioavailability (parameters)and dissolution (parameters) areexplored ….Pharmacokinetic (bioavailability) –Pharmacodynamic (clinical) correlationis presumed ….UVB
  83. 83. In vivo vs in vitro systeminherent differences ….9What is the ultimate objective ofIVIVC ??To set up IVIVC based dissolution test(in vitro test) quality specifications toensure batch-to-batch consistencywith respect to quality !!!!UVB
  84. 84. CorrelationCan dissolution andbioavailability be correlated ?Misconception/Myth:-Amount of drug dissolved should equate(correlate) with amount of drug bioavailable(absorbed)The pursuit should be:-Are the changes in the bioavailabilityperformances between formulationspredictable in/from the respective dissolutionperformances of these products ?UVB
  85. 85. Module IXIn Vitro - In Vivo CorrelationsPart 3: Regulatory Perspective
  86. 86. Basics of In Vitro – In Vivo CorrelationsIVIVC …1• Classes of In Vitro – In VivoCorrelations– Pharmacological Correlations:based on clinical observations– Semi-quantitative Correlations:based on blood levels or urinaryexcretion data– Quantitative Correlations:resultant to absorption kinetics– Most of the published correlationsfall within the second class; themost valuable are those based onabsorption kinetics.UVB
  87. 87. Basics of In Vitro – In Vivo Correlations IVIVC….2• Essentially there are twobasic types of correlationsthat are employed whilecomparing in vivo – in vitrodata:– Quantitative Correlations– Rank Order CorrelationsUVB
  88. 88. Basics of In Vitro – In Vivo Correlations IVIVC….3• IVIVC – Poor Correlations– Differences seen in BA datanot seen in dissolution data– Order of rates reversed– Significant differences seen indissolution tests NOTobserved in BA data– Dissolution inconsistent withBA dataUVB
  89. 89. Basics of In Vitro – In Vivo Correlations IVIVC….4• Methods for Correlation– Numerical deconvolution /convolution– Statistical moment analysis– Model-dependent methods• Loo-Reigelman• Wagner-Nelson– Regression type correlationof distinct single parametersUVB
  90. 90. Basics of In Vitro – In Vivo CorrelationsIVIVC ….5– Human data supplied for IVIVC– Bioavailability studies should haveenough subjects– IVIVCs use the fasted state– Any in vitro method can be used– Preferred apparatus (1, 2, 3 or 4)– CDER should be consulted if other isusedUVB
  91. 91. Basics of In Vitro – In Vivo Correlations IVIVC….6•Deciphering Levels ofCorrelation•Level A / I–Analogous parameters–Complete profiles–Degree of superimposability• Time-scaling factorUVB
  92. 92. Basics of In Vitro – In Vivo Correlations IVIVC….7•Deciphering Levels ofCorrelation•Level B / II–Analogous parameters–Complete profiles–Model independent parameters–PK / Kinetic parametersrepresenting entire functionUVB
  93. 93. Basics of In Vitro – In Vivo Correlations IVIVC….8• Deciphering Levels ofCorrelation• Level C / III– Analogous parameters– Complete profiles– Relevant PK / kineticparameters• Level D / IV (!)– Accidental correlationsUVB
  94. 94. Basics of In Vitro – In Vivo Correlations IVIVC….9• Developing a Correlation:Procedure for developing aLevel A correlation“The plasma level or urinary excretiondata obtained in the definitive BA studyof the MR DDS are treated by adeconvolution procedure. The resultingdata may represent the drug input rateof the dosage form. It is alsoconsidered to represent in vivodissolution when the rate controllingstep of the DDS is it dissolution rate.Any deconvolution procedure (i.e.Mass balance or mathematicaldeconvolution) will produce acceptableresults.”UVB
  95. 95. Basics of In Vitro – In Vivo Correlations IVIVC….10• Developing a CorrelationThe batch used in the pivotalBA study is subjected to invitro dissolution evaluation,and the effect of varying thedissolution conditionsinvestigated–Variables to be studied• Apparatus• Mixing intensity• Dissolution mediaUVB
  96. 96. Basics of In Vitro – In Vivo Correlations IVIVC….11• Developing a Correlation– In vitro dissolution curve is then comparedto the drug input rate curve (degree ofsuperimposibility)• Position one curve on another• Comparing equation constants• Plot fraction absorbed in vivo versusfraction released in vitro• For Level A, result would be a straightline with a slope (may be) equal to 1• Intercept probably not 0 due to lag timeUVB
  97. 97. Basics of In Vitro – In Vivo Correlations IVIVC….12• Developing a Correlation– Behavior such that drug release isindependent of variables studied• General, robust Level A correlation– Behavior such that drug release isdependent on variables of dissolution• Establish conditions that best correlatewith in vivo [discriminatory]UVB
  98. 98. Module XIn Vitro - In Vivo CorrelationsPart 4: Data Analyses- In vitro and In vivo
  99. 99. Pharmaceutical Systems (Types)– Physical property based• Disintegration• Non-disintegrating– Functional property based (regulatorybased)• Immediate release• Modified release– Enteric coated– Others (PR/SR/CR/DR/ER/…)– Carrier system based• Solid (dissolution testing required)• Semi-solid (dissolution testing required)• Liquids (dissolution testing requiredexcept for true solutionsBCS-UVB
  100. 100. Computation ofDissolutionMeasurement– Cumulative amount of drugreleased as a function of time– Percent dose related as afunction of time– Amount remaining to bereleased as a function of timeUVB
  101. 101. • Dissolution Profile: DesirableCharacteristics– Complete– Frequently / AdequatelySampled– Sensitive / Discriminatory– Reproducible– ValidatedUVB
  102. 102. • Questions– Should we be interested inUSP specifications– What is dissolution profiling?How does it differ from pHprofiling?– Should we be interested inparticular regions of thedissolution profile?– Is a complete dissolutionprofile necessary? If yes, when(Development or QC)?UVB
  103. 103. Sampling DuringDissolution Testing– Frequent and adequate– Should capture critical regions ofprofile– Provide for discrimination andsensitivity analysis– User friendlyUVB
  104. 104. Dissolution Profile(Critical Components)– IR products• Early-phase dissolution (critical)• Later-phase dissolution (lesscritical)– MR products (technology-basedproducts)• Early-phase dissolution (critical)• Middle-phase dissolution (lesscritical)• Later-phase dissolution (critical)UVB
  105. 105. Bioavailability Assessment• PK Parameters (BA Investigations)– Absolute Bioavailability [F]• F = [(AUC po) * Dose po] / [(AUCi.v) * Dose i.v]– Relative Bioavailability [f]• F or F rel = [(AUC test) * Dose test]/ [(AUC ref) * Dose ref]– Half-Life = 0.693 / terminal phase rateconstant= 0.693 / β– AUC (Cp as a function of time)• AUC t1 – t2 = 0.5 * (c1 + c2) * (t2 –t1)……..– AUC 0 → * = AUC 0 → t last + AUC t last → inf= AUC 0 → t + tail-endcorrection= AUC 0 → t + Cp last / β
  106. 106. Bioavailability Assessment• Statistical AnalysisAssumptions– Subjects are randomlyassigned to study sequences– Variances between groupsand treatments arecomparable– Main effects for standardminimum 3 x 3 crossoverstudy should be additive (nointeractions)UVB
  107. 107. Bioavailability AssessmentSingle Dose– AUC 0 → t (trapezoidal rule)– AUC 0 → * (trapezoidal rule +tail-end correction)– Cmax– Tmax– Terminal Phase• Rate constant (apparent)• Half-life (apparent)UVB
  108. 108. Bioavailability Assessment• Single-Dose Fasting Three-Way Crossover BA Study– Subjects• Minimum 24, healthy, 18 – 50 years old,within 10 – 15% of IBW (male or non-pregnant females)• Written, informed consent required– Overnight fast for at least 10 hours– Restrictions– Blood Samples– Subject monitoringUVB
  109. 109. Bioavailability Assessment• Sampling and SamplingInterval: Reasons andRationale– Adequate characterization ofbioavailability• Rate: Cmax and Tmax• Extent: AUC 0-t AUC 0-*– Complete characterization ofbioavailability• 3 – 5 half-lives post administration– Characterization of critical biologicalprocesses• Absorption: predominantly pre-Cmax• Elimination: terminal phase or the 4thor 5th half-life period– Acquire adequate number of points onbio-profile– Clinically relevant
  110. 110. Bioavailability Assessment• Sampling Interval – SomeRules of Thumb– Adequate and subject friendly (asmuch as possible)– Frequent, but not necessary(minimum 4 – 5 samples duringeach phase is sufficient)– Should be able to capture the Cmaxregion– Should be able to capture the cleanterminal phase– More frequent during absorptionphase– Less frequent during distributionand elimination phaseUVB
  111. 111. Module XIIn Vitro - In Vivo CorrelationsPart 5: Setting up IVIV Correlation
  112. 112. Frequently Employed Techniquesfor Correlating IVIV Data– Numerical Deconvolution /Convolution– Statistical Moment Analysis– Model-Dependent Methods By• Loo-Riegelman• Wagner-Nelson– Regression-Type Correlationof distinct in vivo and singlein vitro parametersUVB
  113. 113. Analogous– Functional similarity– Parametric similarity– Process similarity– Complete profiles– Degree of superimposibilityUVB
  114. 114. Analogous Parameter Employedin IVIVC DeterminationsIn Vitro In VivoAUC AUCKr, Kd Ka, Kd, KrTinf, Tmax CmaxF(t), T(F),MRTFa(t), T(Fa)MDT MRTUVB
  115. 115. Sample Data Set 1
  116. 116. Sample Data Set 1
  117. 117. Sample Data Set 1
  118. 118. Sample Data Set 2• 3 Uniqueformulations(F1, F2, andF3) Figure 2. Average In-VitroDissolution(APIRecovered)0.00%20.00%40.00%60.00%80.00%100.00%0 20 40 60 80 100 120Time (hrs)AverageIn-VitroDissolution,(APIRecovered)Error Bars = +/- %CVFormul-ationAverage %CVIn-VitroPerformance% LCF1 5.34 109F2 7.88 91F3 11.82*98*Exceeds FDArecommendation <10%F1F3F2f2 values betweenformulations are all < 50,indicative of dissimilardissolution
  119. 119. Curve Fitted EquationsSample Data Set 2In-Vitro DissolutionY = -a*exp(-k*t) + bWhere:Y = % DrugDissolvedt = Timea = The span ofdissolution( 100)b = The asymptoteof thedissolutioncurve ( 100)k = The dissolutionrate constantFormulationk R2F1 0.815 99.8%F2 0.078 100.0%F3 0.021 99.7%
  120. 120. In-Vivo Results (PK)Sample Data Set 2• 3 Unique In-Vivo PKResults (F1,F2, and F3)Pharmacokineticsof API in Swine and Human01234567890 0.25 0.5 1 2 4 6 8 12 18 24 36 48 72 120 144 168 336 504 672Time (hrs)APIConcentrationinBlood(ng/mL)Error Bars = +/- Standard DeviationRelative% DiffCmax%DiffAUCF1 vsF247 35F2 vsF350 22F2F3F1F1 - Human
  121. 121. Curve Fitted EquationsSample Data Set 2• In-Vivo (PK)C = a + b*exp(-0.5*(ln(t/c)/d)^2)Where:– C = Concentrationof API (ng/ml)– t = Time (hrs)– a, b, c, and d areconstants thatdefine theconcentration curveFormulationR2F1(Swine)96.8%F2 99.0%F3 97.2%F1(Human)99.7%
  122. 122. Level A: Fractional Response TimesSample Data Set 2Graph of In-Vitro Dissolution and In-Vivo PK FractionalResponse Times(FRT)y = 6.39x- 1.78R2= 0.98y = 0.87x- 2.62R2= 0.97y = 0.40x- 4.43R2= 0.95-5051015202530350 10 20 30 40 50 60 70 80 90In-Vitro Dissolution FRT, (hours)In-VivoPK(%AUC)FRT,(hours)F2F3F1 Fraction Dissolved (In-Vitro) vsFraction Absorbed (In-Vivo, PK)
  123. 123. Module XIIIn Vitro - In Vivo CorrelationsPart 6: Applications and Perspectives
  124. 124. IVIVC:Applications and Perspectives• Setting QC Specifications• Biowaivers• Dose-proportionate formulations• Performance Based IVIVCsUVB
  125. 125. Notes ……
  126. 126. Notes ……
  127. 127. Module XIIIConcluding Remarksand Q and AUmesh V. Banakar, PhD
  128. 128. • Is it possible to simulate in vivoconditions within the in vitrodissolution test in the laboratory ….• It surely is challenging ……..• More important is – Theunderstanding of thephysiological/biological, i.e., in vivoconditions is of paramountimportance to design anappropriate biorelevant dissolutiontest ….• The quest for such adissolution test continues ….
  129. 129. Thinking is capitalEnterprise is the wayHard work is the solutionHis Excellency Dr. A.P.J. AbdulKalamHon. President of IndiaNov. 28,2007
  130. 130. THANK YOUDhanyawaad !!muito obrigado !!!!umeshbanakar@juno.com
  131. 131. Please ….• Only easy/simplequestions that Ican answer !!!!
  132. 132. Umesh V. Banakar, PhD++ 317 440 7784 (mobile)++ 317 334 0174umeshbanakar@juno.com

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