QbD for Pharma Products Development

QbD for Pharma Products Development

1. QbD for Pharma Products Development
Dr. Basavaraj K. Nanjwade
Principal Scientist
Trroy Life Sciences Pvt Ltd
C-14, New Town Yelhanka
Bangalore-560064, Karnataka, India
1Aditya Bangalore Institute of Pharmacy Education and Research10/03/2018

2. Content
•Components of the Drug Product
•Drug Product
•Manufacturing Process Development
•Container Closure System
•Microbiological Attributes
•Compatibility
•Quality Target Product Profile
•Critical Quality Attributes
•Risk Assessment: Linking Material Attributes and Process Parameters
to Drug Products CQAs
•Design Space
•Control Strategy
•Product Lifecycle management and Continual Improvement
•Submission of Pharmaceutical Development and Related Information
in Common Technical Document (CTD) Format (3)
2Aditya Bangalore Institute of Pharmacy Education and Research10/03/2018

3. Quality by Design
A Systematic approach
•To development
•That begins with predefined objectives
•Emphasizes product and process understanding
•Process control
•Based on sound sciences and quality risk
management
3Aditya Bangalore Institute of Pharmacy Education and Research10/03/2018

4. Quality by Design
•Pharmaceuticalqualityreferstoproductfreeof
contaminationandreproduciblydeliversthetherapeutic
benefitpromisedinthelabeltotheconsumer.
•TheQualityofthepharmaceuticalproductcanbe
evaluatedbyinvivoorinvitroperformancetests.
•Qualitybydesignassuresinvitroproductperformance
andInvitroproductperformanceprovidesassuranceof
invivoproductperformance.
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5. QbD Approach
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6. QbD Tools
•Design of experiments (DoE)
•Risk assessment
•Process analytical technology (PAT)
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7. Design of experiments (DoE)
•Asystematicseriesofexperiments,
•InwhichpurposefulchangesaremadetoINPUTfactorsto
identifycausesforsignificantchangesintheOUTPUT
responses.
•Determiningtherelationshipbetweenfactorsandresponses
toevaluateallthepotentialfactorssimultaneously,
systematicallyandspeedily.
•Withcompleteunderstandingoftheprocesstoassistin
betterproductdevelopmentandsubsequentprocessscale-up
withpretendingthefinishedproductqualityand
performance.
7Aditya Bangalore Institute of Pharmacy Education and Research10/03/2018

8. Risk assessment
•Basic Risk Management Facilitation Methods
•Failure Mode Effects Analysis (FMEA)
•Failure Mode, Effects and Criticality Analysis (FMECA)
•Fault Tree Analysis (FTA)
•Hazard Analysis and Critical Control Points (HACCP)
•Hazard Operability Analysis (HAZOP)
•Preliminary Hazard Analysis (PHA)
•Risk Ranking and Filtering
•Supporting Statistical Tools
8Aditya Bangalore Institute of Pharmacy Education and Research10/03/2018

9. Process analytical technology (PAT)
•Multivariate tools for design, data acquisition
and analysis
•Process analyzers
•Process control tools
•Continuous improvement and knowledge
management tools
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10. Quality by End Product Testing
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11. Quality by Design
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12. Traditional approach & Enhanced QbD approach
Aspects Non-QbD QbD
Pharmaceutical
Development
Empirical, Random,
Focus on optimization
Systematic, Multivariate
experiments, Focus on control
strategy and robustness
Manufacturing
Process
Fixed Adjustable within design space,
managed by company’s quality
systems
Process Control Some in-process testingPAT utilized, Process operations
tracked and trended
Product SpecificationPrimary means of quality
control, based on batch
data
Part of the overall quality control
strategy, based on desired product
performance
Control StrategyBy testing and inspectionRisk-based control strategy , real-
time release possible
12Aditya Bangalore Institute of Pharmacy Education and Research10/03/2018

13. Components of the Drug Product
•DrugSubstance:Thephysicochemicalandbiological
propertiesofthedrugsubstancethatcaninfluencethe
performanceofthedrugproductandits
manufacturability,orwerespecificallydesignedinto
thedrugsubstance(e.g.,solidstateproperties),should
beidentifiedanddiscussed.
•Excipients:Theexcipientschosen,theirconcentration,
andthecharacteristicsthatcaninfluencethedrug
productperformance(e.g.,stability,bioavailability)or
manufacturabilityshouldbediscussedrelativetothe
respectivefunctionofeachexcipient.
13Aditya Bangalore Institute of Pharmacy Education and Research10/03/2018

14. Drug Product
•FormulationDevelopment:Anyexcipient
rangesincludedinthebatchformula
•Overages:Amountofdrugsubstancelistedin
thebatchformula.
•PhysicochemicalandBiologicalProperties:
Selectionofdissolutionvs.disintegration
testing
14Aditya Bangalore Institute of Pharmacy Education and Research10/03/2018

15. Manufacturing Process Development
•Themanufacturingprocessesusedtoproduce
batchesforpivotalclinicaltrials(safety,
efficacy,bioavailability,bioequivalence)or
primarystabilitystudies.
•Processrobustnesscanbeusefulinrisk
assessmentandriskreduction
15Aditya Bangalore Institute of Pharmacy Education and Research10/03/2018

16. Container Closure System
•Thechoiceandrationaleforselectionofthecontainer
closuresystemforthecommercialproduct(described
in3.2.P.7)shouldbediscussed.
•Thechoiceofmaterialsforprimarypackagingshould
bejustified.
•Justificationforsecondarypackagingmaterials
shouldbeincluded,whenrelevant.
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17. Microbiological Attributes
•Theselectionandeffectivenessofpreservative
systemsinproductscontainingantimicrobial
preservative
•Forsterileproducts,theintegrityofthecontainer
closuresystemasitrelatestopreventing
microbialcontamination
•Antimicrobialpreservativeeffectivenessshould
bedemonstratedduringdevelopment.
17Aditya Bangalore Institute of Pharmacy Education and Research10/03/2018

18. Compatibility
•Thecompatibilityofthedrugproductwith
reconstitutiondiluents(e.g.,precipitation,
stability)shouldbeaddressedtoprovide
appropriateandsupportiveinformationforthe
labeling.
•Thisinformationshouldcovertherecommended
in-useshelflife,attherecommendedstorage
temperatureandatthelikelyextremesof
concentration.
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19. Quality Target Product Profile (QTPP)
•A prospective summary of
•The quality characteristics of a drug product
•That Ideally will be achieved to ensure the
desired quality,
•Taking into account Safety and Efficacy of the
drug product.
Aditya Bangalore Institute of Pharmacy Education and Research 1910/03/2018

20. QTPP of Solution
QTPPElement Target Justification
Dosage Form Solution Same dosage form
Dosage Design IR Formulation Label claims
Route of Administration Oral/External
Dosage Strength
Drug Product Quality Attributes
Appearance
Assay
Content Uniformity
Impurities
pHof system
Microbiallimits
Antimicrobial content
Antioxidant content
Extractable
Viscosity/Specification
Primaryand Secondary Packaging
Pharmaco-Kinetics
Ease of Storage and Distribution
Stability and Self Life
Patient Acceptance and Patient Compliance
20Aditya Bangalore Institute of Pharmacy Education and Research10/03/2018

21. Critical Quality Attribute (CQA)
ACQAisa
•Physical,
•Chemical
•Biological,or
•Microbiologicalpropertyorcharacteristicthatshould
bewithinanappropriatelimit,range,ordistributionto
ensurethedesiredproductquality.
•CQAsaregenerallyassociatedwiththedrugsubstance,
excipients,intermediates(in-processmaterials),and
drugproduct.
Aditya Bangalore Institute of Pharmacy Education and Research 2110/03/2018

22. CQA of Solution
QualityAttributes of Drug ProductTarget In this a
CQA?
Physical Appearances Colour, Odor&taste etc Yes
Identification Monograph Yes
Rheological properties(viscosity/specific
gravity
As Per Pharmacopoeia Yes
Assay 90.0 to 110.0% Yes
Weight variation/Content UniformityLabelled claim(NMT 15.0%) Yes
Antimicrobial Preservative contentAs per Pharmacopoeia Yes
Antioxidant preservative content As per specification Yes
pH of System As per Pharmacopoeia Yes
Impurities/Degradation Product As per ICH Q3A&Q3B Yes
Microbiological Limits Conforms to USP,BP, IP Yes
Extractable Conforms to USP, BP, IP Yes
Dissolution As per specification Yes
22Aditya Bangalore Institute of Pharmacy Education and Research10/03/2018

23. Risk Assessment: Linking Material Attributes
and Process Parameters to Drug Products CQAs
•Riskassessmenttoolscanbeusedtoidentify
andrankparameters(e.g.,process,equipment,
inputmaterials)withpotentialtohavean
impactonproductquality,basedonprior
knowledgeandinitialexperimentaldata.
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24. Risk Assessment
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25. Critical Material Attribute (CMA)
•Independentformulationvariablesi.e.
Physicochemicalpropertiesofactive(drug
substance)&inactiveingredients(excipients)
•AffectingCQAsofsemi-finishedand/or
finisheddrugproduct.
Aditya Bangalore Institute of Pharmacy Education and Research 2510/03/2018

26. Critical Process Parameter (CPP)
•Independentprocessparameter
•MostlikelytoaffecttheCQAsofan
intermediateorfinisheddrugproductand
thereforeshouldbemonitoredorcontrolled.
•Toensuretheprocessproducesthedesired
qualityproduct.
Aditya Bangalore Institute of Pharmacy Education and Research 2610/03/2018

27. Critical Material Attribute (CMAs)
Physico-Chemical
Properties
Critical Material Attribute
(CMAs)
Failure Mode Effect
Analysis (FMEA)
(Critical Event)
Physical Properties
Solid State Form Different Polymorph/form
Particle Size Distribution
(PSD)
High PSD
Moisture content High water content
Residual solvents High residual solvent
Chemical Properties
Solubility Different salt/Form
Volatility High
Process Impurities Less Purity
Chemical Stability Poor
Biological PropertiesMicrobial Content High
27Aditya Bangalore Institute of Pharmacy Education and Research10/03/2018

28. Critical Material Attribute (CMAs)
Excipient (InactiveIngredient)Critical Material Attribute Failure Mode (Critical Event)
Vehicles/Solvents Quantity of Vehicle/Solvent Less than optimum
More than optimum
Hydrocolloid (Suspending agent as
a structured vehicle)
Source of Hydrocolloid Natural
Concentration of Hydrocolloid
Less than optimum
More than optimum
Surfactants(As
Solubilizing/agents)
Ionic Nature of surfactant Cationic/Anionic in nature
Concentration of Surfactant
Less than optimum
More than optimum
Buffering Agent
pH of the Buffer
Within Neutral Range
Within Acidic/Basic Range
Anti-Microbial Concentration of Anti-Microbial Less than optimum
Anti-Oxidant Concentration of Anti-oxidant Less than optimum
Sweetener/Flavouring agent Concentration of sweetener/FlavourNot Optimum
Coloringagent Concentration of ColoringAgent Not Optimum
Aditya Bangalore Institute of Pharmacy Education and Research 2810/03/2018

29. Critical Process Parameters (CPP)
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Unit Operations Critical Process Parameters (CPPs) Failure Mode (Critical Event)
Vehicle/Solvent Preparation Storage & Distribution
Rate of Addition Higher than Optimum
Filtration Rate
Heating Rate (Temp Time) Lower than Optimum
Higher than Optimum
Mixing Rate (Speed Time)
With Co-Solvents
Lower than Optimum
Solubilization of solid (API+Presevative) by surfactantsOrder of addition Incorrect
Impeller Design & Position Improper
Mixing Rate (Speed Time) Lower than Optimum
Heating Rate (Temp Time) Higher than Optimum
Supporting by structured Vehicles Order of Addition Incorrect
Rate of Addition Higher than Optimum
Mixing Rate (Speed Time) Lower than Optimum
Organoleptic addition with mixing Order of Addition Incorrect
Mixing Rate (Speed Time) Lower than Optimum
Heating Rate (Temp Time) Higher than Optimum
pH Adjustment with Buffer & Final Volume make up with vehicle &
final mixing
Rate of Addition Higher than Optimum
Impeller Design & Position Improper
Mixing Rate (Speed Time) Lower than Optimum
Heating Rate (Temp Time) Lower than Optimum
Higher than Optimum
Ultrafiltration in Colloidal mill
Type & Principle of Filter Improper
Filter Screen size Incorrect
Rate of Filtration Higher than Optimum
Filling, Capping & Sealling with nitrogen purging
Filling rate (Speed Time) Not Optimum
Higher than Optimum
Nitrogen purging rate Lower than Optimum
Capping & sealing rate Lower than Optimum
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30. Design of Experiments (DoE)
•Asystematicseriesofexperiments
•Inwhichpurposefulchangesaremadetoinputfactorsto
identifycausesforsignificantchangesintheoutputresponses
&
•Determiningtherelationshipbetweenfactorsandresponsesto
evaluateallthepotentialfactorssimultaneously,systematically
andspeedily;
•Withcompleteunderstandingoftheprocesstoassistinbetter
productdevelopmentandsubsequentprocessscale-upwith
pretendingthefinishedproductqualityandperformance.
Aditya Bangalore Institute of Pharmacy Education and Research 3010/03/2018

31. Design Space
The Multidimensional Combination and
Interaction of
•Critical Material Attributes and
•Critical Process Parameters that have been
demonstrated to provide assurance of quality.
Aditya Bangalore Institute of Pharmacy Education and Research 3110/03/2018

32. Design Space
1.Selection of Variables
2.Describing a Design Space in a Submission
3.Unit Operation Design Space(s)
4.Relationship of Design Space to Scale and
Equipment
5.Design Space Versus Proven Acceptable
Ranges
6.Design Space and Edge of Failure
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33. Design Space
33Aditya Bangalore Institute of Pharmacy Education and ResearchTemperature
Pressure
Large square shows the ranges tested in the DOE
Red area shows points of failure
Green area shows points of success.
10/03/2018

34. 1. Selection of Variables
•Adescriptionshouldbeprovidedintheapplicationof
theprocessparametersandmaterialattributes
consideredforthedesignspace,thosethatwere
included,andtheireffectonproductquality.
•Therationaleforinclusioninthedesignspaceshould
bepresented.
•Insomecases,itishelpfultoprovidealsothe
rationaleastowhysomeparameterswereexcluded.
•Knowledgegainedfromstudiesshouldbedescribed
inthesubmission.
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35. 2. Describing a Design Space in a
Submission
•Adesignspacecanbedescribedintermsofrangesof
materialattributesandprocessparameters,orthrough
morecomplexmathematicalrelationships.
•Itispossibletodescribeadesignspaceasatime
dependentfunction(e.g.,temperatureandpressure
cycleofalyophilisationcycle),orasacombinationof
variablessuchascomponentsofamultivariatemodel.
•Scalingfactorscanalsobeincludedifthedesignspace
isintendedtospanmultipleoperationalscales.
•Analysisofhistoricaldatacancontributetothe
establishmentofadesignspace.
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36. 3. Unit Operation Design Space(s)
•Theapplicantcanchoosetoestablish
independentdesignspacesforoneormoreunit
operations,ortoestablishasingledesign
spacethatspansmultipleoperations.
•Whileaseparatedesignspaceforeachunit
operationisoftensimplertodevelop,adesign
spacethatspanstheentireprocesscanprovide
moreoperationalflexibility.
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37. 4. Relationship of Design Space to
Scale and Equipment
•Whendescribingadesignspace,theapplicantshouldconsider
thetypeofoperationalflexibilitydesired.
•Adesignspacecanbedevelopedatanyscale.
•Theapplicantshouldjustifytherelevanceofadesignspace
developedatsmallorpilotscaletotheproposedproduction
scalemanufacturingprocessanddiscussthepotentialrisksin
thescale-upoperation.
•Iftheapplicantproposesthedesignspacetobeapplicableto
multipleoperationalscales,thedesignspaceshouldbe
describedintermsofrelevantscale-independentparameters.
•Dimensionlessnumbersand/ormodelsforscalingcanbe
includedaspartofthedesignspacedescription.
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38. 5. Design Space Versus Proven
Acceptable Ranges
•Acombinationofprovenacceptableranges
doesnotconstituteadesignspace.
•However,provenacceptablerangesbasedon
univariateexperimentationcanprovideuseful
knowledgeabouttheprocess.
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39. 6. Design Space and Edge of Failure
•Itcanbehelpfultodeterminetheedgeoffailurefor
processparametersormaterialattributes,beyond
whichtherelevantqualityattributescannotbemet.
•However,determiningtheedgeoffailureor
demonstratingfailuremodesarenotessentialpartsof
establishingadesignspace.
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40. Design Space for drying
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41. Process Analytical Technology (PAT)
ASystemfor-
•Designing,
•Analysing&
•ControllingManufacturingthroughTimely
Measurements(i.e.,duringprocessing)of
CriticalQualityandPerformanceattributesof
rawandin-processmaterialsandprocesses
withthegoalofensuringfinalproductquality.
Aditya Bangalore Institute of Pharmacy Education and Research 4110/03/2018

42. ControlStrategy
•AplannedsetofcontrolsforCMAsandCPPs-
derivedfromcurrentproductandprocess
understanding
•DuringlabScaleDevelopmentalStage
•ScaledUpExhibit-SubmissionStagethat
ensuresprocessperformanceandproduct
quality
•DuringCommercialStage
Aditya Bangalore Institute of Pharmacy Education and Research 4210/03/2018

43. Control Strategy for CMA
Factors CMA’s Purpose of Control
Active Pharmaceutical Ingredient (API) CMA
Polymorphic Form 2values To ensure batch to batch consistency in Dissolution
Excipient CMA
Vehicle Grade To ensure consistence compatibility, purity & Micro.Stab.
Surfactant Type (Tween 80) To ensure batch to batch consistency in solubility,pour
ability, Physical Stability & Compatibility
Concentration (%w/w)
Hydrocolloids Source (CMA)
Concentration (%w/w)
Sweetener Concentration (%w/w)To ensure batch to batch consistent Patient Acceptance &
Compliance
Flavor Concentration (%w/w)
Color Concentration (%w/w)
Anti-Microbial Concentration (%w/w)To ensure batch to batch consistency Chemical &
Microbiological stability
Anti-Oxidant Concentration (%w/w)
Buffer Concentration (%w/w)
Aditya Bangalore Institute of Pharmacy Education and Research 4310/03/2018

44. Control Strategy for CPP
Factors (s) CPPs Purpose of Control
Vehicle/Solvent Preparation with
Sweetener, Flavor, Color
Heating Temperature To ensure consistance
compatibility, acceptability,purity
& Micro. Stability
Mixing Time
Controlled Solubilizationby
surfactant& hydrocolloids
Heating Temperature To ensure batch to batch consiste
cy in Solubility, Pour ability,
Physical Stability & Compatibility
Mixing Time
pH Adjustment with Buffer &
Final Volume make up with
vehicle & final Mixing
Heating Temperature To ensure batch to batch
consistency Chemical &
Microbiological stability
Mixing Time
Ultrafiltration Particulate Matter Screen
Size
To ensure batch to batch purity to
warrant Safety
Microbial Filter Screen Size
Filling, Capping & SealingTemperature To ensure Chemical Stability
Vacuum Pressure with
Nitrogen Purging
Aditya Bangalore Institute of Pharmacy Education and Research 4410/03/2018

45. Product Lifecycle Management and
Continual Improvement
•Throughouttheproductlifecycle,companieshave
opportunitiestoevaluateinnovativeapproachesto
improveproductquality
•Processperformancecanbemonitoredtoensurethatitis
workingasanticipatedtodeliverproductquality
attributesaspredictedbythedesignspace.
•Expansion,reduction,orredefinitionofthedesignspace
couldbedesiredupongainingadditionalprocess
knowledge.
•Changeofdesignspaceissubjecttoregional
requirements.
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46. Continual Improvement
Risk Review and Risk Communication
Lifecycle
Management
Formulation
R&D
Analytical
R&D
Regulatory
Affairs
Manufacturing
Plant
Quality
Assurance
Quality
Control
Aditya Bangalore Institute of Pharmacy Education and Research 4610/03/2018

47. SUBMISSION OF PHARMACEUTICAL
DEVELOPMENT (3)
•Quality Risk Management and Product and Process
Development
•Design Space
•Control Strategy
•Drug Substance Related Information
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48. Quality Risk Management and Product
and Process Development (3.1)
•Qualityriskmanagementcanbeusedatdifferentstages
duringproductandprocessdevelopmentand
manufacturingimplementation.
•Theassessmentsusedtoguideandjustifydevelopment
decisionscanbeincludedintherelevantsectionsofP.2.
•Forexample,riskanalysesandfunctionalrelationships
linkingmaterialattributesandprocessparametersto
productCQAscanbeincludedinP.2.1,P.2.2,andP.2.3.
•Riskanalyseslinkingthedesignofthemanufacturing
processtoproductqualitycanbeincludedinP.2.3.
48Aditya Bangalore Institute of Pharmacy Education and Research10/03/2018

49. Design Space (3.2)
•Asanelementoftheproposedmanufacturingprocess,thedesignspace(s)
canbedescribedinthesectionoftheapplicationthatincludesthe
descriptionofthemanufacturingprocessandprocesscontrols(P.3.3).
•Ifappropriate,additionalinformationcanbeprovidedinthesectionofthe
applicationthataddressesthecontrolsofcriticalstepsandintermediates
(P.3.4).
•Theproductandmanufacturingprocessdevelopmentsectionsofthe
application(P.2.1,P.2.2,andP.2.3)areappropriateplacestosummarizeand
describeproductandprocessdevelopmentstudiesthatprovidethebasisfor
thedesignspace(s).
•Therelationshipofthedesignspace(s)totheoverallcontrolstrategycanbe
discussedinthesectionoftheapplicationthatincludesthejustificationof
thedrugproductspecification(P.5.6).
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50. Control Strategy (3.3)
•Thesectionoftheapplicationthatincludesthe
justificationofthedrugproductspecification
(P.5.6)isagoodplacetosummarizetheoverall
drugproductcontrolstrategy.
•However,detailedinformationaboutinput
materialcontrolsandprocesscontrolsshouldstill
beprovidedintheappropriateCTDformat
sections(e.g.,drugsubstancesection(S),control
ofexcipients(P.4),descriptionofmanufacturing
processandprocesscontrols(P.3.3),controlsof
criticalstepsandintermediates(P.3.4)).
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51. Drug Substance Related Information (3.4)
•IfdrugsubstanceCQAshavethepotentialtoaffect
theCQAsormanufacturingprocessofthedrug
product,somediscussionofdrugsubstanceCQAs
canbeappropriateinthepharmaceuticaldevelopment
sectionoftheapplication(e.g.,P.2.1).
Aditya Bangalore Institute of Pharmacy Education and Research 5110/03/2018

52. Benefits of QbD
•Better understanding of the process.
•Less batch failure.
•More efficient and effective control of change.
•Return on investment / cost savings.
•An enhance QbD approach to pharmaceutical
development provides opportunities for more flexible
regulatory approaches.
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53. Benefits of QbD
•Consistent product quality
•Reduced risk of recalls
•Real-time release
•Cost Reduction
•Reduced inventories
•Less waste
•Higher yields
•Increased process understanding resulting in more efficient production
processes
•Faster process development, upscaling and tech transfer
•Regulatory flexibility, relief and easier regulatory approach
•Improved clinical outcome quality
•Easy Technology Transfer
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54. Manufacturing changes within the approved design space
•Reductionofpost-approvalsubmissions.
•Betterinnovationduetotheabilitytoimproveprocesseswithout
resubmissiontotheFDAwhenremainingintheDesignSpace.
•Moreefficienttechnologytransfertomanufacturing.
•Greaterregulatorconfidenceofrobustproducts.
•Risk-basedapproachandidentification.
•Innovativeprocessvalidationapproaches.
•Lessintenseregulatoryoversightandlesspost-approval
submissions.
•Fortheconsumer,greaterdrugconsistency.
•Moredrugavailabilityandlessrecall.
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55. Manufacturing changes within the approved design space
•Improved yields, lower cost, less investigations, reduced testing, etc.
•Time to market reductions: from 12 to 6 years realized by amongst
others.
•First time right: lean assets management.
•Continuous improvement over the total product life cycle (i.e.
controlled, patient guided variability).
•Absence of design freeze (no variation issues).
•Less validation burden.
•Real time controls (less batch controls).
•Realistic risk perceptions.
•Contributes substantially to realize the better, cheaper and safer
mandate.
Aditya Bangalore Institute of Pharmacy Education and Research 5510/03/2018

56. QbD activities within FDA
•InFDA’sOfficeofNewDrugQualityAssessment
(ONDQA),anewrisk-basedpharmaceuticalquality
assessmentsystem(PQAS)wasestablishedbasedonthe
applicationofproductandprocessunderstanding.
•ImplementationofaQuestion-basedReview(QbR)
ProcesshasoccurredinCDER’sOfficeofGenericDrugs.
•ImplementationofQbDforaBiologicLicense
Application(BLA)isprogressing.
56Aditya Bangalore Institute of Pharmacy Education and Research10/03/2018

57. International Conference on
Harmonization (ICH)
•Pharmaceutical Development Q8 (R2)
•Quality Risk Management Q9
•Pharmaceutical Quality System Q10 (Science-
based and risk-based approaches)
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58. International Conference on
Harmonization (ICH)
•ThedifferencebetweenQbDforNDAand
ANDAproductsismostapparentatthefirst
stepoftheprocess.
•ForanNDA,thetargetproductprofileisunder
developmentwhilefortheANDAproductthe
targetproductprofileiswellestablishedbythe
labellingandclinicalstudiesconductedto
supporttheapprovalofthereferenceproduct.
58Aditya Bangalore Institute of Pharmacy Education and Research10/03/2018

59. RPN = Probability* Severity* Detectability
Probability Severity Detectability
Probability of Risk occurrence
can reduced by systematic
series of experiments through
Designing of Experiments
(DoE)
Severity of Risks
could not be reduced
Detectability of Riskcan
increased by implementation of
automatic inline
Process Analytic Technology
(PAT)
Which generated safe and
optimized ranges of CMAs &
CPPs with respect to desired
CQAs par overlaid Design
Space, Where all the desired in
process & finished product
CQAs are met simultaneously
Which ensured timely
measurementof critical quality
and performance attributes of
raw and in-process materials or
parameters to control the
quality of finished product.
Aditya Bangalore Institute of Pharmacy Education and Research 59
RPN (Risk Priority Number) more than 30 seek critical attention for DoE for possible failure
10/03/2018

60. Total Risk Priority Number (RPN)
ProbabilitySeverity Delectability Score
Very UnlikelyMinor Always Detected 01
Occasional Moderate Regular Detected 02
Repeated Major Likely Detected 03
Regular Extreme Normally not Detected 04
Aditya Bangalore Institute of Pharmacy Education and Research 60
Risk Priority Number (RPN) more than 30 seek critical attention for DoE for possible failure
10/03/2018

61. Aditya Bangalore Institute of Pharmacy Education and Research 61
Quality Target product Profile (QTPP)
-Therapeutic Equivalence for Generic Drug Product
-Pharmaceutical Equivalence (same dosage form, route of administration, strength and same quality)
-Bio-Equivalence (same pharmacokinetics in terms of C
max, AUC to reference product)
Critical Quality Attributes (CQAs)
-Quality: Assay, Uniformity of Dosage units
-Safety: Impurities (Related substances), Residual Solvents, Microbiological limits
-Efficacy: Dissolution & Absorption &
-Multidisciplinary: Patient Acceptance & Compliance
Quality Risk Assessment of CMAs & CPPs with CQAs
-Risk Identification by Ishikawa Fishbone
-Risk Analysis by Relative Risk Based Matrix Analysis
-Risk Evaluation by Failure Mode Effective Analysis (FMEA)
Designing of Experiments (DoE) & Design Space
For Screening & Optimization of CMAs &CPPs with respect to CQAs by superimposing contour plot to generate Overlay Plot (Proven acceptable Ranges & Edges of
failure) based upon desired ranges of Responses
Process Analytical Technology (PAT)
For continuous automatic IN LINE analyzing & Feed Back controlling critical processing through timely measurements of CMA & CPAsby INLINE Analyzers with auto
sensors with the ultimate goal of consistently ensuring finished product quality with respect to desired CQAs
Implementation of Control Strategy
For Controls of CMAs, CPPs within Specifications by Real Time Release Testing, Online Monitoring System, Inline PAT Analyzersbased upon previous results on
development, Scale Up. Exhibit/Validation batches.
10/03/2018

62. 62Aditya Bangalore Institute of Pharmacy Education and Research
THANK YOU
10/03/2018