ilfd lyophilization process validation 04-14-10 one slide pe

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


Tech Transfer / Scale-up to Manufacturing:Qualified EquipmentConfirmed process design/reproducible parametersBatch uniformityConsistent product qualities


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)


Dry Cake AppearanceColor, density, uniformity, shrinkage, collapse, meltback

Moisture ContentAverage and range


ReconstitutionTechniqueComplete dissolution

Constituted Solution AppearanceClarityColor


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

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0

10

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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

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-14

-12

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-8

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-4

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400 420 440 460 480 500

Time (minutes)

Tem

pera

ture

(o C

)

PAR: 5o < Target

PAR: 5o > Target


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-18

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-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

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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)


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-8

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400 420 440 460 480 500

Time (minutes)

Tem

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(o C

)

PAR: 5o < Target

PAR: 5o > Target Action Level: 4o > Target

Action Level: 4o < Target

Alert Level: 2o < Target

Alert Level: 2o > Target


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0

400 420 440 460 480 500

Time (minutes)

Tem

pera

ture

(o C

)

40

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60

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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


Capability of reproducible commercial manufacture

CGMP compliant proceduresSuccessful completion prior to commercial distribution


Capability of reproducible commercial manufacture

CGMP compliant proceduresSuccessful completion prior to commercial distributionLaboratory and pilot studies can provide additional assurance


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

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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

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-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

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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

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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

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600

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1200

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0 20 40 60 80 100 120 140

Time (Minutes)

Pres

sure

(Mic

rons

)

PRESSURE

Pressure Control TestPressure Control Test


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96

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106

108

110

20 25 30 35 40 45 50 55 60

Time (Minutes)

Pres

sure

(Mic

rons

)

PRESSURE


490

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494

496

498

500

502

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506

508

510

60 65 70 75 80 85 90 95

Time (Minutes)

Pres

sure

(Mic

rons

)

PRESSURE


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.


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


Product Temperature UniformityProduct Temperature Uniformity

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10

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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

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4:06

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5:27

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6:48

:00

8:09

:00

9:30

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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


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


“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


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

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0 200 400 600 800 1000 1200 1400 1600 1800

Time (minutes)

Tem

pera

ture

(o C

)

0

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1000

1200

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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.


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


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


Primary Drying− Shelf temperature

(soaks and ramps)

− Chamber pressure− Product temperature

(Phase transition temperature)

− Condenser temperature


Secondary Drying− Shelf temperature

(soaks and ramps)

− Chamber pressure− Product temperature

(Phase transition temperature)

− Condenser temperature

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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



Equipment general descriptionHeating and cooling systemsVacuum systemGas used to break vacuum (sterile)Temperature controlling system



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



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


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


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


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.

ilfd lyophilization process validation 04-14-10 one slide pe

Documents

process product

finished product testing

process knowledge

process dataroutine

rangeproduct characteristics

storage ph target

lyophilization technology

established envelopecollect