CONTENTS

Introduction

1 Thermal Validation and Why it is Important 1Jeanne Moldenhauer

Introduction 1Physical Validation of Sterilization Processes 2Uses of Temperature Distribution and Heat Penetration Studies 5

Installation and commissioning of equipment 5Installation Qualification (IQ) 6Engineering evaluations 7Operational Qualification (OQ) 7

Empty chamber temperature distribution 7Mapping studies 9Heat penetration studies 11

Performance Qualification (PQ) 11Temperature distribution studies 11Heat penetration studies 12Maintenance of validation status 13

Troubleshooting aberrant cycles 13Maintenance support 14

Conclusion 14

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ReferencesAbout the Author

2 Steam Sterilization Process ValidationJames Agalloco

IntroductionValidation Supportive Activities

Equipment Qualification (EQ)Installation Qualification (IQ)Operational Qualification (OQ)Validation maintenanceSterilization process development

Performance Qualification (PQ)Introduction to sterilizationComponent mappingDetermination of sterilization process objectiveEmpty chamber studiesLoad definitionTemperature penetration/biological indicator studiesValidation using the overkill methodValidation using the BB/BI and bioburden methodsAdditional perspectives on terminal sterilizationSterilization-in-place (SIP)

Equivalence in ValidationSterilizer equivalenceLoad equivalenceContainer equivalenceFormulation equivalenceProduct equivalenceMultiple equivalenceTime equivalenceEquivalence for sterilization processesEstablishing equivalence

Biological IndicatorsValidation Maintenance/Change Control/Re-validationConclusionAppendix 1: Steam Sterilization Overkill Acceptance CriteriaReferencesAbout the Author

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3 Regulatory Expectations for ThermalValidation — USA 51Jeanne MoldenhauerIntroduction 51United States Regulatory Expectations 51

Calibration 53Sterilizers using steam or air–steam mixtures 54Sterilizers using superheated water 54Minimum sterilization processing 55Testing of sterilization processes 55

Heat distribution studies 55Heat penetration studies 55

Sterilization process design 56Sterilization process controls 57

Expectations of U.S. Regulators During Inspections 59SterilizationValidation Document to be Submitted in Support

of Product Applications 63Heat distribution (also called temperature distribution) and

heat penetration studies 63Thermal monitors 63The effects of loading on thermal input 64Information to be included in the batch record 65

Sterilization in Support of Aseptic Processing Applications 65The qualification of sterilizers 65

Requirements for thermal validation studies 66Sterilization of equpment, containers and closures 67Equipment controls and instrument calibration 68

Routine operation 69Conclusion 69Acknowledgements 69References 69About the Author 70

4 European Expectations For Thermal Validation 71Roland Marie Frédéric GuinetIntroduction 71Validation 73Risk Assessment 77European Pharmacopoeia (EP) and European Medicines

Agency (EMA) 79EU GMP Annex 1 82

General principles for all sterilisation processes 82

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General principles for heat sterilisation processes 83Moist heat specific points 84

Annex 1 §94 84Annex 1 §95 84Annex 1 §96 95

Dry heat specific points 95Performance Qualification of Sterilisation Processes 95

General recommendations for moist heat, dry heat and SIP 95Definition of loads to be sterilised or depyrogenised 86Physical qualification 87Biological qualification 90

Review and Approval of Validation 92Ongoing Control 92

Routine monitoring and/or release 92System suitability 93Change control 93Periodic requalification/revalidation 94

Conclusion 95ReferencesAbout the Author

5 The EMEA’s Decision Tree for Selectionof Sterilisation MethodsJeanne MoldenhauerIntroductionBackgroundFlow Chart Explaining the Sterilization Choices for

Aqueous ProductsConclusionReferencesAbout the Author

6 Importance of Accurate Measurements inThermal Validation StudiesGöran BringertIntroductionIndustry TrendsRegulations, Standards and Guidance for Validation

Quality Management SystemsEuropean Community

Risk Assessment and Risk Management

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Corrective Action Preventive Action (CAPA)Application Specific RegulationsEnvironmental TestingSummary of Standards and Regulations

Process measurement uncertainty requirementsOverall validation system Test Uncertainty Ratio (TUR)

Regulatory Requirements for CalibrationCalibrationCalibration Uncertainty and Calibration RatiosCalibration Procedure

Pre-study calibrationPost-study calibrationPost-study verification

Calibration BasicsTransfer standardTemperature reference

Transfer Calibration ErrorReducing Stem Conduction ErrorsPressure MeasurementThermal Process Validation

FDA definition of process validationWhat Is Critical?

Risk assessmentValidation Concept Definitions

ValidationValidation planValidation protocolValidation reportValidation procedure

Lethality CalculationProcess Temperature UniformityOverall Validation System UncertaintyError SourcesSensor DesignResponse TimeThermocouple SpecificsTemperature Sensors

InsulationSimplified Thermoelectric TheoryNonhomogeneous RegionsResistance Thermometers (RTDs)Validation Studies

Temperature distribution studies

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Thermal mappingHeat penetration studies

Measuring System ErrorsAbout the Author

7 Performance of Thermal Validation StudiesKevin TruppIntroductionDetails for Moist Heat Sterilization Applications

Saturated steam sterilizersSteam Air Mixture (SAM) sterilizersSuperheated water sterilizersCommodity processorsSteam In Place (SIP)

Details for Dry Heat Sterilization ApplicationsDetails for Gaseous and Sterilization/Decontamination

ApplicationsEthylene OxideVaporized Hydrogen Peroxide (VHP)

Details for Controlled Environmental ApplicationsCommon Issues Related to Thermal ValidationSummary and ConclusionsAbout the Author

8 Practical Aspects of Thermal Validation forMoist Heat SterilizationAngela S. Coon and Michael J. SadowskiIntroductionMoist Heat Sterilization Process ApplicationsDistribution Temperature and Heat Penetration TemperatureTypes of Thermal Probes and Datalogging Systems used to

Monitor Temperature Distribution and Heat PenetrationTemperature in the Development andValidation of MoistHeat Sterilization Processes

Wired Temperature Datalogging SystemsWirless Temperature Datalogging SystemSterilization Science: Principles of Microorganism Inactivation

SterileSterilitySterilizationProbability of a Non-Sterile Unit (PNSU)

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Biological indicatorDT-valuez-valueF-valueFPHYSpore Log Reduction (SLR)

Development of Moist Heat Sterilization ProcessesCharacterization of Process LoadSelection of the Moist Heat Sterilization Process TypeSaturated Steam ProcessesSaturated Steam Gravity Displacement CyclesAir Overpressure ProcessesSteam–air Mixture (SAM) ProcessSuperheatedWater ProcessSteam CharacteristicsTemperature Distribution StudiesConsiderations in the Development of Efficient Loading PatternsHeat Penetration StudiesProbing TechniquesCold Spot StudiesPorous/Hard GoodsMaster Site/Master Solution Determination StudiesDetermination of Sterilization Cycle ParametersKey and Critical Parameters

Heat up conditionsExposure (dwell) temperatureExposure (dwell) pressureExposure (dwell) time

Physical Lethality Requirements from Regulatory StandardsPhysical Lethality Requirements Based on the Overkill Design

ApproachPhysical Lethality Requirements Based on the Product Specific

Design ApproachDetermination of Exposure Time Required to Deliver Minimum

Lethality RequirementsPost Exposure ConditionsLimitations of Temperature Probes in the Prediction of

Microbiological Inactivation During Qualification of MoistHeat Sterilization Processes

Performance Qualification (PQ)Predecessors to Performance QualificationPhysical QualificationMicrobiological Qualification

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PNSU CalculationsRequalificationOptimization of the Moist Heat Sterilization ProcessesSummaryReferencesAbout the Authors

9 Analysis of Heating and Cooling DataDr. Irving PflugBrief Background to Conduction–Heat TransferHeating and Cooling Objects or Products in ContainersConduction–Heat TransferSolution to a Problem of Unsteady-State, Conduction–Heat

Transfer Using the Sphere as the ExampleGeometrical Shape

Solution to the Problem of Unsteady-State-Conduction–HeatTrasfer in an Infinite Cylinder

Convection–Heat TransferHeating Products in ContainersAnalysis of Natural Convection–Heat Transfer Using a

Newtonian-Heating ApproachUnsteady-State Heat Transfer Graphically, Conduction

and ConvectionExample Heating and Cooling GraphsPlotting and Analyzing Heating and Cooling Data

The Semilogarithmic-Graph PaperThe Temperature Scale

The Heating-MediumTemperaturePlotting the Data PointsDrawing a Straight Line Through the Data PointsA Discussion of Autoclave or Retort Come-Up Time, the

Corrected-Zero Time, and the Use of the Corrected-Zero Time in Calculating the Fh-Value

Autoclave TemperatureValidationLiterature CitedAbout the Author

Glossary

Index

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