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International Society of Lyophilization- Freeze Drying
Midwest Chapter Annual Meeting
Contemporary Approaches to Lyophilization Process Validation
(in the Product Lifecycle)
Edward Trappler, Lyophilization Technology, Inc.
Early DevelopmentPre-formulationAPI CharacterizationFormulationPresentation
Phase I ClinicalShort term stabilityProduct characterization
Phase II ClinicalLong term stabilityProduct specificationsProcessing experience
Phase III ClinicalDevelopment reportTechnology transferLarge scale batches
Bench scaleBench scale
Lab scaleLab scale
Pilot scalePilot scale
ManufacturingManufacturing
Development PathwayDevelopment Pathway
Governing FactorsGoverning Factors
Product QualityEconomicsCompliance
Product Life CycleProduct Life Cycle
Development:Appropriate / reproducible process parametersConsistent finished product quality attributesAdequate long term stability
Product Life CycleProduct Life Cycle
Tech Transfer / Scale-up to Manufacturing:Qualified EquipmentConfirmed process design/reproducible parametersBatch uniformityConsistent product qualities
Product Life CycleProduct Life Cycle
Routine Manufacturing:Operate within an established envelopeCollect and analyze product and process dataRoutine review and statistical analysisState of control for processConsistent critical quality attributes
Development Objectives
Address and DocumentClear intended outcome of processEstablished critical independent processing parameters (CPP)Assigned key dependent processing parameters (KPP)Well defined critical quality attributes (CQA)Appropriate in-process and finished product testingSupporting stability data
Development ObjectivesDevelopment ObjectivesProduct and Process Product and Process
Knowledge and UnderstandingKnowledge and Understanding
Product DevelopmentDosage FormDosage FormCritical Quality Attributes (CQA)Critical Quality Attributes (CQA)
Process DesignDefine Critical Process Parameters (CPP)Identify Key Process Parameters (KPP)
Product CharacteristicsCompounding ProceduresCompounding Procedures
Order of additionMixingpH adjustmentPhysico-chemical aspects
Product Characteristics Bulk Solution StorageBulk Solution Storage
Storage conditionsExpiration
Product Characteristics Low Temperature AnalysisLow Temperature Analysis
Phase TransitionEutectic, glass transition (Tg’), collapse
MorphologyAmorphous or crystalline
Product CharacteristicsFinished Product QualitiesFinished Product Qualities
Morphology / Thermal PropertiesDried Cake AppearanceResidual Moisture RangeConstituted Solution Attributes
Product Characteristics Finished Product QualitiesFinished Product Qualities
MorphologyAmorphous or crystalline
Phase Transition TemperatureCrystalline melt, glass transition (Tg)
Product Characteristics Finished Product QualitiesFinished Product Qualities
Dry Cake AppearanceColor, density, uniformity, shrinkage, collapse, meltback
Moisture ContentAverage and range
Product Characteristics Finished Product QualitiesFinished Product Qualities
ReconstitutionTechniqueComplete dissolution
Constituted Solution AppearanceClarityColor
Product Characteristics Finished Product QualitiesFinished Product Qualities
Product AssayInitialConstituted solution (after storage)
pHTarget and Range
Process Parameters
Establish critical independent parametersShelf (inlet) temperatureChamber pressureTime
Identify key dependent parametersProduct temperatureCondenser temperature
Target Lyophilization ParametersTarget Lyophilization Parameters
-50
-40
-30
-20
-10
0
10
20
30
40
0 200 400 600 800 1000 1200 1400 1600 1800
Time (minutes)
Tem
pera
ture
(o C
)
0
200
400
600
800
1000
1200
1400
1600
1800
2000
Mic
rons
Chamber Pressure
Shelf Temperature
Product Temperature
Threshold Temperature
Proven Acceptable RangeProven Acceptable RangeBoundary ParametersBoundary Parameters
Define acceptable critical parameter range
Proven Acceptable Range (PAR)Boundary Conditions
Lyophilization Parameter PARLyophilization Parameter PAR
-20
-18
-16
-14
-12
-10
-8
-6
-4
-2
0
400 420 440 460 480 500
Time (minutes)
Tem
pera
ture
(o C
)
PAR: 5o < Target
PAR: 5o > Target
Target Lyophilization ParametersTarget Lyophilization Parameters
-20
-18
-16
-14
-12
-10
-8
-6
-4
-2
0
400 420 440 460 480 500
Time (minutes)
Tem
pera
ture
(o C
)
40
50
60
70
80
90
100
110
120
Mic
rons
PAR: 20 µHg < Target
PAR: 20 µHg > Target
Proven Acceptable RangeProven Acceptable RangeBoundary Boundary StudiesStudies
Three batches at target conditionsProcess conducted at “ideal” parametersProcess conducted at “ideal” parameters
Four batches at boundary conditionsHigh and low shelf temperaturesHigh and low shelf temperaturesHigh and low chamber pressuresHigh and low chamber pressures
Proven Acceptable RangeProven Acceptable RangeBoundary StudiesBoundary Studies
Three batches at target conditionsDemonstrates reproducibilityDemonstrates reproducibilityConfirms consistent product qualitiesConfirms consistent product qualities
Four batches at boundary conditionsEnvelopes processing conditionsEnvelopes processing conditionsEstablishes proven acceptable rangeEstablishes proven acceptable range
-80
-60
-40
-20
0
20
40
0 200 400 600 800 1000 1200 1400 1600 1800
Time (Minutes)
Tem
pera
ture
(o C)
0
100
200
300
400
500
600
700
800
900
1000
Shelf Temperature
Chamber Pressure
Proven Acceptable Range Proven Acceptable Range --Acceptable Boundary ConditionsAcceptable Boundary Conditions
Proven Acceptable RangeProven Acceptable RangeBoundary ParametersBoundary Parameters
Define acceptable critical process parameter range (CPP)
Verify with product analysis and stability (CQA)
Target Lyophilization ParametersTarget Lyophilization Parameters
-20
-18
-16
-14
-12
-10
-8
-6
-4
-2
0
400 420 440 460 480 500
Time (minutes)
Tem
pera
ture
(o C
)
PAR: 5o < Target
PAR: 5o > Target Action Level: 4o > Target
Action Level: 4o < Target
Alert Level: 2o < Target
Alert Level: 2o > Target
Target Lyophilization ParametersTarget Lyophilization Parameters
-20
-18
-16
-14
-12
-10
-8
-6
-4
-2
0
400 420 440 460 480 500
Time (minutes)
Tem
pera
ture
(o C
)
40
50
60
70
80
90
100
110
120
Mic
rons
PAR: 20 µHg < Target Action Level: 15 µHg < Target
Action Level: 15 µHg > Target Alert Level: 10 µHg > Target
Alert Level: 10 µHg < Target
PAR: 20 µHg > Target
Proven Acceptable RangeBoundary Conditions
Alert Level: If these conditions continue the process will approach an Action Level.
Action Level: If these conditions continue the process will approach a Boundary Condition.
Process Qualification
Demonstrate and document capability of reproducible commercial manufacture
Qualification of unit operationPerformance Qualification
Process Qualification
Capability of reproducible commercial manufacture
CGMP compliant proceduresSuccessful completion prior to commercial distribution
Process Qualification
Capability of reproducible commercial manufacture
CGMP compliant proceduresSuccessful completion prior to commercial distributionLaboratory and pilot studies can provide additional assurance
Process Qualification
Address and DocumentIntended outcome of processCritical Processing Parameters (CPP)Key Processing Parameters (KPP)Critical Quality Attributes (CQA)In-process and finished product testingExtensive sampling and stability dataAdditional analysis may be appropriate
Equipment QualificationGoals
Verify that the equipment is adequate and appropriate.
Document the design, construction and installation.
Demonstrate the proper functions and performance
Prove that the equipment does what it is intended to do
Equipment QualificationScope and Objectives
Evaluation of each system function required for processing, including verifying reproducibility and consistency (uniformity) of conditions and outcome.
Assure that the system performance is adequate to support the process intended.
Benefits
Effective project managementSuccessful integrationEconomicsCompliance
Equipment Qualification
Maximum Cooling and Heating RateShelf Temperature ControlShelf Temperature UniformityCondenser Cooling RateCondenser Capacity
Equipment Qualification
System Evacuation RatePressure ControlSublimation / Condensation RateProcess Control / Data AcquisitionLyophilization Cycle Run
Shelf Temperature
Maximum Cooling and HeatingHeat Transfer Fluid SystemRefrigeration for CoolingHeaters for Warming
Shelf Temperature UniformityMonitoring Locations
Five locations on each shelf
Each corner andgeometric center
Shelf Temperature UniformityMonitoring Locations
Five locations on each of the shelves
Maximum Shelf Cooling / Heating TestMaximum Shelf Cooling / Heating Test
Shelf Inlet
-60
-40
-20
0
20
40
60
80
0 50 100 150 200 250 300 350 400 450 500
Time (Minutes)
Tem
pera
ture
(°C
)
0100200
300400500600700
8009001000
Setpoint
Shelf Inlet
Shelf Temperature
Cooling Control and UniformityControl at loading temperaturesCooling rate determinationControl at low temperatures
Shelf Temperature
Heating Control and UniformityHeating rate determinationControl at high temperaturesControl at intermediate temperatures
Shelf Cooling/Heating/Control TestShelf Cooling/Heating/Control Test
-60
-40
-20
0
20
40
60
80
0 500 1000 1500 2000 2500
Time (Minutes)
Tem
pera
ture
(°C
)
Condenser Cooling
Cooling Rate− Rate of chilling to process limit
Blank-Off Temperature− Ultimate temperature achieved
FD7 Condenser CoolingStudy X60301
-80
-70
-60
-50
-40
-30
-20
-10
0
10
0 10 20 30 40 50 60 70 80
Time (Minutes)
Tem
pera
ture
(°C
)
COND 1 COND 2
Condenser Cooling TestCondenser Cooling Test
Vacuum Pumping
Pull-Down Rate− Rate of evacuation to process limit
Blank-Off Pressure− Ultimate pressure achieved
FD-7 Chamber Evacuation Testing Study X41201
-2000
0
2000
4000
6000
8000
10000
12000
14000
0 5 10 15 20 25 30 35 40
Time (min)
Tem
pera
ture
(C)
CH VAC
Chamber Evacuation RateChamber Evacuation Rate
Pressure Control
Set Point Control During Drying− Minimum, maximum and selected
intermediate set points
Pressure Control During Stoppering− Setpoint control for vial headspace pressure
0
200
400
600
800
1000
1200
1400
0 20 40 60 80 100 120 140
Time (Minutes)
Pres
sure
(Mic
rons
)
PRESSURE
Pressure Control TestPressure Control Test
Pressure Control TestPressure Control Test
90
92
94
96
98
100
102
104
106
108
110
20 25 30 35 40 45 50 55 60
Time (Minutes)
Pres
sure
(Mic
rons
)
PRESSURE
Pressure Control TestPressure Control Test
490
492
494
496
498
500
502
504
506
508
510
60 65 70 75 80 85 90 95
Time (Minutes)
Pres
sure
(Mic
rons
)
PRESSURE
Pressure Control TestPressure Control Test
990
992
994
996
998
1000
1002
1004
1006
1008
1010
86 91 96 101 106 111 116 121
Time (Minutes)
Pres
sure
(Mic
rons
)
PRESSURE
Sublimation - Condensation
Sublimation / Condensation Rates− Produce maximum sublimation rate achievable
Condenser Capacity− Sublime quantity of water equal to total condenser
capacity at the maximum sublimation rate
Process Control
ActivitiesComputer validationInput and output checksSoftware development documentationVerification of programsVerification of alarms
hierarchy and response“failure challenges”
Data Acquisition
Data Acquisition Systems− Prove that the system is capable of the resolution, accuracy and precision necessary for adequate control and documentation of the process
Lyophilizer Uniformity Studies
ObjectiveDemonstrate uniformity of conditions and product attributes unique to lyophiles throughout batch, independent of location within the lyophilizer.
GoalAssurance of reproducible processing conditions and consistent dried product characteristics with desirable attributes throughout a batch and for every batch, independent of location.
Lyophilizer Uniformity Studies
BenefitsAllows correlation of sample temperature during processing to dried product attributes.
Opportunity for statistical analysis.
Identify location within lyophilizer as points for future monitoring and finished product sampling.
Lyophilizer Uniformity StudiesLyophilizer Uniformity Studies
Location in lyophilizer– Includes product temperature range at
critical times during process.
– Correlate to dried product attributes.
– Most representative and extreme location in the lyophilizer.
Lyophilizer UniformityMonitoring & Sampling Locations
Five locations on each shelf(filled with “product”)
Monitor for product temperature and evaluate dried product attributes
Lyophilizer UniformityMonitoring & Sampling Locations
Five locations on each of the shelves
Product Temperature UniformityProduct Temperature Uniformity
-50
-40
-30
-20
-10
0
10
20
30
40
Tim
e
14:3
6:00
15:5
7:00
17:1
8:00
18:3
9:00
20:0
0:00
21:2
1:00
22:4
2:00
0:03
:00
1:24
:00
2:45
:00
4:06
:00
5:27
:00
6:48
:00
8:09
:00
9:30
:00
10:5
1:00
12:1
2:00
13:3
3:00
14:5
4:00
16:1
5:00
17:3
6:00
18:5
7:00
20:1
8:00
21:3
9:00
23:0
0:00
0:21
:00
1:42
:00
3:03
:00
4:24
:00
5:45
:00
7:06
:00
8:27
:00
9:48
:00
11:0
9:00
12:3
0:00
Left Location A Shelf 02 Location E Shelf 11 Location A Shelf 12 Centre Shelf 07 Location E Shelf 08
Centre Shelf 10 Location A Shelf 06 Location A Shelf 09 Location E Left Shelf 05 Location E Right Shelf 03
Centre Shelf 13 Centre Shelf 04 Centre Outlet Shelf 01 Centre Inlet Shelf 01 Centre Shelf 01
Centre Inlet Shelf 13 Centre Outlet Shelf 13 Centre Inlet Shelf 07 Centre Outlet Shelf 07
End of Freezing
End of Primary Drying
End of Secondary Drying
Lyophilizer Uniformity Studies
Use of “model” or actual productActual product formulationPlacebo vials spiked with active product vialsUse of a Surrogate
Surrogate Product AttributesSurrogate Product Attributes
PresentationSufficient size (fill volume)Ease of inspectionEase of inspection
Model formulationDiscernable melt back or collapseDistinguishable residual moisture
RepresentativeMay emulate actual productSimilar to range of products
Critical Dried Product QualitiesCritical Dried Product Qualities
Dried cake appearanceExpected appearanceAbsence of melt back or collapseAbsence of melt back or collapse
Acceptable Residual MoistureAverageRange
ReconstitutionTimeSolution appearance
Lyophilizer UniformityResults of Monitoring & Sampling
Five locations on each of the shelves
“Most Extreme”
“Most Representative”
Shelf 1
Shelf 3
Lyophilizer Uniformity StudiesLyophilizer Uniformity Studies
Locations in lyophilizer– “Most representative” reflects
the majority of the batch.– “Most extreme” is the outlier
that envelopes the entire batch.
FDA Definition:Expectation for Validation
Establishing documented evidence which provides a high degree of assurance that a specific process will consistently produce a product meeting its predeterminedspecifications and quality attributes.
Validation for ComplianceExample of an Objective
The objective of validation for (product XYZ) is to show that product manufactured and tested in accordance with Master Batch Record ABC and Validation Protocol 123 will consistently meet its predetermined specifications and quality attributes. This will be done using 3 consecutively manufactured batches of product.
Heather Pederson, former Pre-Approval Inspection Program Manager, USFDA (Newark District)
Manufacturing Process Control
PROCESSES TO INCLUDEFormulationFillingVial TransferLyophilizationSealing / CappingVisual Inspection
Development to ManufacturingDevelopment to ManufacturingSHOULD BE:
BIO-BATCHES(PRODUCT SPECIFICATIONS)
SCALE UP BATCHES(PROCESS PARAMETERS)
DEVELOPMENT REPORT
VALIDATION PROTOCOL
VALIDATION BATCHES
VALIDATION REPORT
OFTEN IS:
BIO-BATCHES
SCALE UP BATCHES
DEVELOPMENT BATCHES
DEVELOPMENT BATCHES
DEVELOPMENT BATCHES
VALIDATION REPORT
Heather Pederson, former Pre-Approval Inspection Program Manager, USFDA (Newark District)
Performance QualificationPerformance Qualification
Address and DocumentIntended outcome of processCritical processing parameters (CPP)Key processing parameters (KPP)Critical quality attributes (CQA)In-process and finished product testingStability data
Performance Qualification StudiesPerformance Qualification Studies
Sequence in processing
Location in lyophilizer
Consistent Product Attributes
Performance Qualification StudiesPerformance Qualification Studies
Sequence in processing– Consistent quality attributes throughout batch
– Sample beginning, middle, and end of fill
– Evaluate dispensed liquid and lyophilized samples.
Potency and Purity AttributesPotency and Purity AttributesLiquid PreparationLiquid Preparation
Evaluate starting bulk liquid attributesMonitor stability of starting liquid product to quantify attributes from beginning to end of batch.Analysis demonstrates achievement of predicted level of quality, purity, efficacy and bulk liquid stability.
Lyophilization as a Unit OperationLyophilization as a Unit Operation
LoadingFreezingPrimary DryingSecondary DryingStoppering
Process Parameters
Established critical independentparameters (CPP)
Shelf (inlet) temperatureChamber pressureTime
Identified key dependentparameters (KPP)
Product temperatureCondenser temperature
Lyophilization ProcessLyophilization Process
-50
-40
-30
-20
-10
0
10
20
30
40
0 200 400 600 800 1000 1200 1400 1600 1800
Time (minutes)
Tem
pera
ture
(o C
)
0
200
400
600
800
1000
1200
1400
1600
1800
2000
Mic
rons
Chamber Pressure
Shelf Temperature
Product Temperature
Threshold Temperature
Potency and Purity AttributesPotency and Purity AttributesLyophilized ProductLyophilized Product
Assess stability of lyophilized attributesVerify lyophilization process does not alter attributes or magnify any differences for the dried product upon long term storage.Analysis demonstrates achievement of predicted level of quality, purity, efficacy and solid state stability.
Performance Qualification StudiesPerformance Qualification Studies
Consistent Product Attributes– Characteristics unique to
lyophilized preparations with potency and purity attributes
– Correlate initial quality attributes with results upon storage.
Performance Qualification
LoadingTraysLoading order & patternShelf temperatureHolding timeProduct temperature &thermocouple placement
Performance Qualification
Loading− Final shelf temperature and range− Time− Product temperature
Performance Qualificaiton
Freezing− Ramps: Average Controlled Rates of Change− Final shelf temperature and range− Time − Product temperature threshold
Performance Qualification
Primary Drying− Shelf temperature
(soaks and ramps)
− Chamber pressure− Product temperature
(Phase transition temperature)
− Condenser temperature
Performance Qualification
Secondary Drying− Shelf temperature
(soaks and ramps)
− Chamber pressure− Product temperature
(Phase transition temperature)
− Condenser temperature
-80
-60
-40
-20
0
20
40
0 200 400 600 800 1000 1200 1400 1600 1800
TIME (Minutes)
TEM
PER
ATU
RE (
C)
0
100
200
300
400
500
600
700
800
900
1000
MIC
RO
NS
SHELF TEMPERATURE
THRESHOLD PRODUCT TEMPERATURE
MAXIMUM CONDENSER TEMPERATURE
CONDENSER TEMPERATURE
PRODUCT TEMPERATURES
CHAMBER PRESSURE
Demonstrated Process ControlDemonstrated Process Control
Performance Qualification ObjectivesSummarySummary
Process ParametersControlling independent and monitoring dependent
process variables assures maintenance within a proven acceptable range.
Product CharacteristicsVerifying consistent achievement of predicted level
of quality, purity, efficacy and stability.
Development for QualityExample of an Objective
Design Excellence (DEX) / Design for Six Sigma (DFSS)
Achieving Design Excellence using a set of design tools and methodologies for improving product and process development to consistently provide reliable and manufacturable products that consistently meet customer requirements.
Denise Hudson, VP Worldwide Process Excellence, J&J Pharmaceutical Group
OpportunityValidation for QualityDesign for Six Sigma
Define
Measure
Analyze
Design
Verify/Validate
Transfer
DefineDevelop Scope and Charter the Project
MeasureGather & Quantify Design Inputs
AnalyzeDevelop and Investigate Conceptual Designs
DesignDevelop Detailed Product Design & Production Process
Verify/ValidateConfirm design outputs meet design input requirements and ensure specifications conform with Intended Uses and Users
SummarySummaryAchieving Design ExcellenceAchieving Design Excellence
Product design and processing conditions are identified during development.Reproducible process parameters and consistent product quality attributes are verified during scale-up and technology transfer.Control and reproducibility of the process to consistently yield product of acceptable quality, purity, efficacy and stability are validated in manufacturing.
Thank you for participating!
ReferencesReferencesGuidelinesGuidelines
Guide to Inspection of Lyophilization of Parenterals (7/93)
Formulation of productsAseptic FiIlingCycle, Controls, ValidationSterilization and Aseptic ProcessingFinished Product Inspection and Testing
ReferencesReferencesInspection DocumentsInspection Documents
Compliance Program Guidance Manual, 7356.002A - Sterile Drug Inspections (9/93)
Identify when using CMOWhen manufacturing in house
Manufacturer of lyophilizerPercentage of products lyophilizedEquipment general descriptionProcessing procedures
ReferencesReferencesInspection DocumentsInspection Documents
Compliance Program Guidance Manual, 7356.002A - Sterile Drug Inspections (9/93)
Equipment general descriptionHeating and cooling systemsVacuum systemGas used to break vacuum (sterile)Temperature controlling system
ReferencesReferencesInspection DocumentsInspection Documents
Compliance Program Guidance Manual, 7356.002A - Sterile Drug Inspections (9/93)
Processing proceduresPreparation of the sterile product for dryingProcedures for protecting product from contamination while loading into lyophilizerHow are stoppers seating in vialsConditions during stoppering – under vacuum, what gas is used and how sterilized
ReferencesReferencesInspection DocumentsInspection Documents
Compliance Program Guidance Manual, 7356.002A - Sterile Drug Inspections (9/93)
Review of production recordsReview at least three production recordsVerify cycle parameters and observed results are within scope of validation studiesIdentify criteria for acceptable vs unacceptable runs: general appearance, moisture, etc
ReferencesReferencesGuidance for IndustryGuidance for Industry
Contents & Format of Chemistry, Manufacturing & Controls Information and Establishment Description Information for a Vaccine or Related Product, Section G (1/99)
A validation summary for lyophilizationNarrative description of the validationCertification of completed IQ and OQValidation data summaryExplanation of all excursions or failuresDeviation reports and results of investigation
ReferencesReferencesGuidance for IndustryGuidance for Industry
Submission of Chemistry, Manufacturing…for Human Plasma Derived Biological Products, Animal or Serum-Derived Products, Part 2, Section III, D (2/99)
A validation summary for lyophilizationNarrative description of the validationCertification of completed IQ and OQValidation data summaryExplanation of all excursions or failuresDeviation reports and results of investigation
ReferencesReferencesGuidance for IndustryGuidance for Industry
Content and Format of Chemistry, Manufacturing …for a Biological InVitro Diagnostic Product, Section II, C, Methods of Manufacturing and Packaging (3/99)
A complete description of the manufacturing process flow…should be provided. This discussion should include a description of:
Vialing / fillinglyophilizationlabelingpackaging
ReferencesReferencesGuidance for IndustryGuidance for Industry
Content and Format of Chemistry, Manufacturing …for a Biological InVitro Diagnostic Product, Section II, C, Stability (3/99)
Stability data supporting the proposed shelf life of the reconstituted in vitro product for all labeled dilutions
ReferencesReferencesRegulationsRegulations
Title 21 CFR, Section 211: “GMP”Title 21 CFR Sections 600
(applicable to product category)601.12: Changes to an Approved Application610.13 Purity (a)(1) Test for Residual Moisture
ReferencesReferencesRegulationsRegulations
211.137 (g) Expiration dating information of reconstituted drugs for investigational use.211.166 (a) (5) Stability Testing. Perform stability testing of drug after reconstitution.
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