Cleaning and Cleaning

Validation Strategies for

Multiproduct Manufacturing
Facilities
John M. Hyde
Chairman and Founder
Hyde Engineering + Consulting, Inc.
Hyde
y Engineering
g g + Consulting
g Europep Limited
22 May 2014
 PresentationOutline
DriversofMultiproductManufacturing
Drivers of Multiproduct Manufacturing
DemographicFactors,TariffsandTradeRestrictions,
NewApproachestoCleaningQualificationand
Monitoring
FDAProcessValidationGuidanceThreeStagesof
Validation
ImportanceofCleaningCycleDevelopment
LabandPilotScaleMethodologies
Lab and Pilot Scale Methodologies
CommercialScaleTestingStrategies
OngoingMonitoring
StatisticalAnalyticalMethodologies
S i i lA l i lM h d l i
ApplicationofPATtoCIPOperations
 DemographicFactors
g p
LifeExpectancy
Lif E t
AverageLifeExpectancyhasIncreasedbyMoreThan
50% in BRIC Countries Since 1940
50%inBRICCountriesSince1940
IncreasedRatesofChronicDiseaseConditions
AgeRelated
g
GeneticPredispositions
IncreasingIncomesandGrowingMiddleClasses
GrowingDevelopingWorldMiddleClassIncome
TranslatesIntoGrowingDemandfor
Biopharmaceutical Products
BiopharmaceuticalProducts
By2035,MoreThan50%ofMiddleClassHouseholds
willbeinIndiaandChina
 InternationalTradeIssues
Tariffs
ManyDevelopingWorldGovernmentsImposeHeavy
TariffsonImportedGoodsIncludingPharmaProducts
PharmaProductsManufacturinginDeveloping
CountriesareOftenGivenPreferredTaxTreatment,
E
EspeciallyforExports
i ll f E
SpecialEconomicZones(SEZs)
OtherTradeRestrictions
IndonesiahasErectedImportBarriers,Through
WithholdingRegulatoryApproval,forPharma
ProductsImports
 DevelopingWorldBiopharma
ManufacturingIncentives
DomesticDemand
GrowingIncomesandMiddleClasses
ExporttoDevelopedCountries
SupplyofLowCostBioSimilars
DemandtoSupportInternationalVaccination
Initiatives
GrowingDemandforLowCostPerDoseProducts
LowerProductionCosts
LaborandEquipmentCostAdvantages
ShorterTimelinestoBringFacilitiesOnline
FactorsImpactingFutureBioManufacturing

HigherTiters
LessCellCultureCapacityRequired
L C ll C lt C it R i d
TherapeuticCompetition
OftenSeveralTherapiesfortheSameDiseaseCondition
Often Several Therapies for the Same Disease Condition
RheumatoidArthritis
GrowthinVaccineDemand
Biosimilars
COGS
Geographics GlobalHealth
Green CO2reduction
Mostwerenotdrivingforces10yearsago
 Cleaning and Qualification Objectives
CleaningandQualificationObjectives

PrimaryOperationalConcerns
Pi O i lC
CleaningConsistency
CleaningQuality
CleaningSafety
CostEffectiveOperations
BasesofAssessmentofValidationStudies
AcceptanceCriteriaBasedUponWellUnderstood
DesignSpace
ScientificallyProvenOperatingRanges
TestingScale Lab,PilotPlant,CommercialPlant
 NewApproachestoCleaning
QualificationandMonitoring
lf d
ExtensiveUtilizationofRiskAnalysisandManagementto
EstablishFocusAreasforCleaningValidationand
O
OngoingMonitoring
i M it i
DevelopmentofExistingandNewInProcessMaterial
Residue Matrix from Laboratory and Pilot Scale Cleaning
ResidueMatrixfromLaboratoryandPilotScaleCleaning
Data
UsageofResidueMatrixDataforDeterminationof
ExtentofFullScaleCleaningValidationTesting(e.g.,
UtilizationofLaboratoryDerivedDataandResidue
M ti
MatricesRatherThanThreeFullScaleRunsforValidation
R th Th Th F ll S l R f V lid ti
ofCleaningforNewProducts)
 NewApproachestoCleaning
QualificationandMonitoring
lf d
GenerationofProductInactivationDatatoJustify
AnalyticalMethodologiesforMultiProductFacilities
ResidueLimitsnot
Residue Limits not BasedUponMACCalculations
Based Upon MAC Calculations
UnlessResiduesContainSignificantLevelsofActive
DrugProduct
g
UsageofPATMethodologiesandDataforBasisofInitial
CleaningValidationStudiesandOnGoingMonitoring
f D fi i R V lid i R
forDefiningReValidationRequirements
i
UtilizationofFDA2011ProcessValidationGuidance
Approaches for Bases of Cleaning Validation Program
ApproachesforBasesofCleaningValidationProgram
NewCleaningPracticesforCleaningof
MultiproductProcessEquipment
l d
ReUseofElastomers BetweenManufacturer
ofDifferentProducts
UtilizationofNormalCleaningCycles
BetweenManufacturerofDifferentProducts
LimitedCleaningVerificationBetween
ManufacturerofDifferentProducts
 TraditionalApproachToValidation
pp
Established,
Established,HighlyControlledProcedure
Highly Controlled Procedure
ThreeConsecutive,SuccessfulCommercialRuns
ConfidencePlacedintheConsistentPerformanceof
Confidence Placed in the Consistent Performance of
theControlledProcedureEveryTime
SomeLateStageCleaningCycleDevelopmentOften
g g y p
OccursDuringValidation
AtTheTimeOfCommercialManufacture
E
Excursions/DeviationsAreEvaluatedandCompared
i /D i ti A E l t d dC d
toHistoricalNorms
Risk Based Approach To Validation
RiskBasedApproachToValidation
FocusedonCleaningCycleDevelopment
ValidationStudiesDesignandExecutionBasedUpon
RiskAnalysisandManagement
EstablishedProcessDesignSpaceProvides
Identification of Critical Control Parameters and
IdentificationofCriticalControlParametersand
BoundaryConditionsforEffectiveandTightProcess
Controls
OngoingMonitoringofCriticalProcessParameters
Ongoing Monitoring of Critical Process Parameters
ProvidesBasesofRiskReviewandManagementWith
OngoingRealTimeConfirmationofProcessOperation
Withi V lid t d D i S
WithinValidatedDesignSpace
 2011 GuidanceBased
2011Guidance BasedPractices
Practices

Newguidancecharacterizesprocessvalidation
d h ld
asalifecycleratherthanadiscreteevent,as
impliedinthedefinitioninthe1987guidance
Newguidancegoesontosaythatprocess
g g y p
validationinvolvesaseriesofactivitiestaking
p
placeoverthelifecycleoftheproductand
y p
process
 2011 Guidance Based Practices
2011GuidanceBasedPractices

N
Newguidancedescribesprocessvalidation
id d ib lid ti
activitiesinthreestages
Stage1:Processdesign
Stage2:Processqualification
Stage3:Continuedprocessverification
Stated
Statedanotherway,processvalidationmaybe
another way, process validation may be
definedas:
ProcessValidation=LabStudies+Development
Process Validation = Lab Studies + Development
History+CommercialScaleManufacturing@
Target Values +OngoingMonitoring
TargetValues Ongoing Monitoring
 Stage 1 CleaningDesign
Stage1 Cleaning Design

TestPlan
l
Authoranexperimentaltestplandescribingthe
approachusedtoconductbenchscalecleaning
h dt d tb h l l i
processdevelopmentalstudiesforpostproduction
residues.
residues
CleaningAgentSelection
Test
Testeachresidueusingadesignedexperimentto
each residue using a designed experiment to
screenalkaline,neutral,andacidicpostproduction
residuesoverarangeoftypicalcleaningprocess
g yp gp
temperaturestodetermineanappropriatecleaning
agentforaparticularpostproductionresidue.
 Stage 1 CleaningDesign
Stage1 Cleaning Design

CleaningProcessDesignSpaceExploration
Usingtheappropriatecleaningagent,explore
combinationsoftemperature,turbulence,and
concentrationtoassesstheresponseofremovalrate
overtypicalrangesoftheseprocessvariables.
WorstCaseResidueEvaluation
Comparetheremovalratesofselectedpost
p
productionresiduestoempiricallydeterminewhich
p y
areworstcasewithrespecttothecleaningprocess.
 Essential Cleaning Parameters
EssentialCleaningParameters
CriticalCleaningControlParameters(CCCPs)
C i i l Cl i C lP (CCCP )
Aninputcleaningparameterthatshouldbecontrolledwithina
meaningfulnarrowoperatingrangetoensurethatcleaningquality
attributesmeettheirspecifications.(Outofrangeresultsmayleadto
cleaningfailures.)
KeyCleaningControlParameters(KCCPs)
Key Cleaning Control Parameters (KCCPs)
Aninputcleaningparameterthatshouldbecarefullycontrolledwithina
narrowrangeandisessentialforcleaningperformance.Doesnotaffect
cleaning cycle efficacy but may affect the efficiency (utility usage time
cleaningcycleefficacy,butmayaffecttheefficiency(utilityusage,time,
etc.)
CriticalCleaningQualityAttributes(CCQAs)
Anoutputvariablethatcannotbedirectlycontrolledbutisanindicator
ofcleaningperformanceandcleaningefficacy.
 CCCPs and CCQAs for Cleaning
CCCPsandCCQAsforCleaning

CleaningProcessInputs:
DemonstrationofConsistentandRealTime
Demonstration of Consistent and Real Time
ControlofCleaningParameters,FlowRate,
Temperature,ContactTime,Conductivity,etc.
CleaningProcessOutputs:
Cl i P O t t
DemonstrationofAbilitytoConsistentlyMeet
Specifications for Cleaning Quality Attributes
SpecificationsforCleaningQualityAttributes,
e.g.,TOC,Conductivity,Bioburden,Endotoxin,
etc.
T i l CIP S t
TypicalCIPSystemAnalogInstrumentation
A l I t t ti

EssentialforControlandOngoingMonitoringof
Cleaning Parameters
CleaningParameters
FactorsAffectingCleaningEfficiencyMeasured
via:
Supply/ReturnTemperature
Supply Flow Rate
SupplyFlowRate
SupplyPressure
Supply/Return Conductivity
Supply/ReturnConductivity
 Testing Methodology
TestingMethodology

5cm

~1in2

5cm

Consistentsoiling CleaningProcessControl
Amountofmaterial PIDTemperatureControl
Reproduciblesurface ControlledAgitation
area PreciselyFormulated
ControlDirtyHoldTime
C t l Di t H ld Ti cleaning solutions
cleaningsolutions
 Determining Reynolds Number
DeterminingReynoldsNumber

- density Agitated Immersion:

- viscosity
N Impeller speed in revolutions per second D 2 N
D Impeller Diameter N =
Re

NRe < 2100 Laminar
NRe > 3000 Turbulent

Example:
T=25C
D = 2
2 (0.0508 m)
= 997 (kg/m3) 2
= 0.0089 poise
N = 64 rpm (1.07
(1 07 rps)
NRe = 3082
Coupon Soiling
CouponSoiling

RepresentativePost
ProductionResidue
AppliedtoCoupon
SoiledCouponDriedto
SimulatePost
ProductionConditions
Coupon Testing
CouponTesting
 Gravimetric Assessment
GravimetricAssessment

LaboratoryMicrobalance
Accuracy0.00005grams
Taremassofcoupons
Amountofresiduespiked
oncoupons
Amountofresidue
remainingaftercleaning
f
assessment
 Range Finding Results
RangeFindingResults
Range Finding Tests
RangeFindingTests
12.00

10 00
10.00

Water25C
Water65C
8.00
RateoofRemoval[mg/seec]

COSACIP9225C
COSACIP9265C
COSACIP7225C
6.00
COSACIP7265C
COSAPUR80
COSA PUR 8025C
25C
COSAPUR8065C
4.00

2.00

0.00
0 15 30 45 60 75 90 105 120 135 150 165 180 195 210 225 240
Duration[sec]
 AverageRem
moval Rate[mgg/sec]

0
1
2
3
4
5
6
7

25
COSACIP72[pH2]

45
COSACIP72[pH2]

65
COSACIP72[pH2]

25
Water[pH7]
DistilledW

45
DistilledW
Water[pH7]

65
DistilledW
Water[pH7]

25
COSAPU
UR80[pH7]

45 COSAPU
UR80[pH7]
1%DetergentandTemperature[C]
65

COSAPU
UR80[pH7]
Average Removal Rate [mg/sec]
AverageRemovalRate[mg/sec]

25

COSACIPP92[pH12]
45

COSACIPP92[pH12]
65

COSACIPP92[pH12]
EffectsofpHandTemperature
Effects of pH and Temperature
 Surface Response Plot
SurfaceResponsePlot

Surface Plot of Rate vs Temp, pH

4
Rate

3
6
pH 60
9 50
40
12 30 Temp
 Box Plot Representation
BoxPlotRepresentation

Boxplot of Rate

5
Rate

Temp 25 45 65 25 45 65 25 45 65
pH 2 7 12
 Contour Plot Representation
ContourPlotRepresentation

Contour Plot of Rate vs Temp, pH

65
Rate
< 2
60 2 3
3 4
55 4 5
5 6
> 6
50
Temp

45
T

40

35

30

25
2 4 6 8 10 12
pH
 Product Fragmentation/Inactivation
ProductFragmentation/Inactivation

Conduct
ConductStudiestoShowFragmentation/
Studies to Show Fragmentation /
InactivationofActiveMoleculebyCleaning
Process
ExposeFormulatedBulkProducttoCleaningSolutions
atUseStrengthandTemperature
g p
AnalyzeResidueswithSDSPageandWesternBlotto
ProveFragmentation/Inactivation
FavorableResultsJustifyNonProductSpecific
ResidueTestingMethods,ReUseofElastomers
g ,
andUtilizationofNormalCIPCyclesBetween
ManufactureofDifferentProducts
 Stage 2 CleaningQualification
Stage2 Cleaning Qualification

Duringthisstage,thecleaningcycledesignisconfirmed
asbeingcapableofeffectiveandreproducibleat
commercialmanufacturingscale
i l f t i l
Cleaningcycleschallengedwithtypicalpostproductionresidues
Dirtyandcleanholdtimesalsoassessed
Di t d l h ld ti l d
Qualificationofthefacility,utilitiesandequipmentis
required
Cleaningsystems,cleanandplantutilitiesandprocess
equipment systems are of primary interest
equipmentsystemsareofprimaryinterest
 Stage 2 CleaningQualification
Stage2 Cleaning Qualification

Usuallyrunatoperatingparametersetpointswithin
provenacceptablerangeordesignspace
Boundaryconditiontestingisnottypicallyperformedatthis
stageasithasbeenassessedinStage1
RequiresadditionalQCtestingto
Requires additional QC testing to prove
prove theprocess
the process
Qualificationtestingrequirestheanalysesofmanymore
samples than for ongoing monitoring of cleaning
samplesthanforongoingmonitoringofcleaning
Riskanalysisusedtodetermineextentoftesting
requirements
Equipmentandresiduegroupingsusedtodeterminetesting
requirements
P i t t C id f Cl
PointstoConsiderforCleaningQualification
i Q lifi ti
AnalyticalMethodsSelection
SamplingMethods
VisualInspection
Residue Limits
ResidueLimits
RoleofRiskAssessmentinDeterminationofExtent
of Cleaning Q alification Testing
ofCleaningQualificationTesting
 SamplingRequirements

AreSwabandRinseSamplesNeeded?
S b d i S l d d?
SomeFirmsCombineRinseSamplesWithRigorous
Vi l I
VisualInspectionOnly
i O l
WhatistheObjectiveofEachSampleType?
HowareWorstCaseSampleSitesIdentified
andJustified?
ForRinseSamples,PointsofMaximumCleaning
SolutionContact
ForSwabSamples,DifficulttoCleanAreasDueto
PhysicalConstraintsorAreasofResidueAccumulation
 SamplingRequirements

RequirementsforRinseSamples
ResiduesIncludeUSPCriteriaandWhatElse?
SpecificAPIResidue,TotalProtein,Bioburden,
Endotoxin?
RequirementsforSwabSamples
R i t f S bS l
ResiduesIncludeSpecificorNonSpecificTesting(e.g.
TOC Total Protein or Specific Assays)?
TOC,TotalProteinorSpecificAssays)?
SwabbingMethodValidation
IncludingLODandLOQ!
g
RecoveryStudy
 Visual Inspection
VisualInspection

DetermineVisualResidueLimit(VRL)
EstablishCriticalParameters
Establish Critical Parameters
ViewingDistance
LightIntensity
Li h I i
ViewingAngle
LightingAngle
Inspector
InspectorQualificationandTrainingare
Qualification and Training are
Crucial
 Acceptance Criteria
AcceptanceCriteria

HowCleanisCleanEnough?
H Cl i Cl E h?
MaximumAllowableCarryover(MAC)Calculations
ToxicityorAlergenicity Data
LOQforAnalyticalMethod
LOQ for Analytical Method
CleaningSystemPerformance
RoleofProductFragmentationfromExposureto
f f
CleaningCycle
ScientificRationaleBehindDecision?
Typical BioPharma AcceptanceCriteria
TypicalBioPharma Acceptance Criteria

Visual
Noresiduepresent.NopoolingorstandingWFI.Vesselisvisiblyclean
and dry
anddry.
RinseWaterSamples
RinseWaterConductivity:1 10S/cm
RinseWaterTOC:<0.5ppm
Bioburden:<10CFU/100mLto1000CFU/100mL
Endotoxin:<0.25EU/mL
/

SurfaceSamples
SurfaceSwabs:<1
f b 2ppm TOCin40mL Diluent
l f
for100cm2 Swabbed
bb d
Area
 Risk Analysis and Management
RiskAnalysisandManagement
Risk
RiskAnalysisandManagementisattheCoreofthe
Analysis and Management is at the Core of the
PrimaryObjectivesofValidation
Risk
RiskAnalysesProvidestheBasesfortheFocusofthe
Analyses Provides the Bases for the Focus of the
ProcessandCleaningValidationPrograms
RiskManagementProvidestheMeansforOngoing
g g g
AssuranceofConsumerSafetyandProductEfficacy
ProcessAnalyticalTechnologies(PAT)CanProvideRisk
R d ti Th
ReductionThroughEnhancedProcessUnderstanding
hE h dP U d t di
andRealTimeFailureDetection
Document The Risk Assessment
DocumentTheRiskAssessment
 Stage 3 ContinuedCleaningVerification
Stage3 Continued Cleaning Verification

O
Ongoingassurancethatcleaningisincontrol
i th t l i i i t l
Monitor,collectinformation,assess,continuous
verification cleaning process improvements
verification,cleaningprocessimprovements
Nolongerrevalidation,insteadongoingperiodic
evaluation
21CFR211.180(e) Annualreviewtodeterminewhether
changesinspecificationsormanufacturingorcontrol
procedures are needed
proceduresareneeded
Studytrends,OOS/OOT
tomakeimprovements
Feedbackintodesignstagefor
significantprocessshiftsorchanges
Monitoring Consistency ProcessCapabilityIndex
MonitoringConsistency Process Capability Index
Capability
Capabilityindexisthetotalspecificationrangedividedby
index is the total specification range divided by
theprocessoperatingvariability,6spread.
Cp=totalspecification/6
l f /
=(USLLSL)/6

Measures
Measureshowclosetheprocessparameteroperatestothe
how close the process parameter operates to the
specification

Cp
Cp=1.33indicatestheprocessvariabilityconsumesonly
1 33 indicates the process variability consumes only
75%ofthespecification
Thespecificationis1.33timestheprocessvariabilityspread

TypicalCpgoalsare1.33 2.0
Capability Index
CapabilityIndex

Amountwithin
Specification
 ProcessMonitoring ControlChartAnalysis

NelsonRules
LloydSNelson,1984
Lloyd S Nelson 1984
WesternElectricRules
TestsforOutofControl
PatternsonControl
Charts
 How Can PAT Apply To Cleaning?
HowCanPATApplyToCleaning?

ControlofCleaningCCPs
CriticalforAssuranceofRepeatable
p
CleaningOperations
AssuranceofCleaningOperationWithin
g p
WellDefinedDesignandOperatingSpaces
RealTimeAdjustmentofCCPsforInput
j p
Variability
ProvidesBasesforCleaningProcess
Provides Bases for Cleaning Process
Improvements
PAT: On Line TOC for Cleaning Verification
PAT:OnLineTOCforCleaningVerification

Final Rinse Final Rinse

Machine with valves Tank

Endrinse

Provides a finger print of process

performance
Avoid cleaningg failure
Avoid excess water use
 Summary
Many
ManySignificantDriversResultinginExtensive
Significant Drivers Resulting in Extensive
MultiproductManufacturing
NewFDAProcessValidationGuidanceProvidesa
VeryGoodFrameworkforEffectiveCleaning
Validation
CleaningProcessDevelopmentisaCrucialElement
Cleaning Process Development is a Crucial Element
RiskAssessmentandManagementareKey
ElementsofProgram
NewApproachResultsinMoreEffectiveCleaning
QualificationandOngoingAssuranceofCleaning
Efficacy
PATAppliedtoCIPSystemsCanResultinImproved
andMoreReliableCleaningOperations
 ContactInfo
JohnM.Hyde,B.Sc.,M.Sc.
P i i lC
PrincipalConsultant
l
ChairmanandFounder
H d E i
HydeEngineering+Consulting,Inc.
i +C lti I

john.hyde@hydeec.com
john hyde@hydeec com
+1.303.641.5468