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Process ValidationProcess ValidationProcess ValidationProcess ValidationProcess ValidationProcess ValidationProcess ValidationProcess Validation
Manufacture ofManufacture ofParenteral Drug ProductsParenteral Drug Products
October 05,2007
Socrates Nelson
Disclaimer : The contents of this presentation are my personal opinion and does not reflect either the policy or the practice of my company.
PharmEng Technology Inc.
Joint CVG/TPD conventionJoint CVG/TPD conventionJoint CVG/TPD conventionJoint CVG/TPD convention
‘‘‘‘Quality by DesignQuality by DesignQuality by DesignQuality by Design’’’’
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Manufacture of 1mg/mlManufacture of 1mg/mlManufacture of 1mg/mlManufacture of 1mg/mlManufacture of 1mg/mlManufacture of 1mg/mlManufacture of 1mg/mlManufacture of 1mg/ml
Dexamethasone Inj. 10mlDexamethasone Inj. 10mlDexamethasone Inj. 10mlDexamethasone Inj. 10mlDexamethasone Inj. 10mlDexamethasone Inj. 10mlDexamethasone Inj. 10mlDexamethasone Inj. 10mlRaw materialRaw materialRaw materialRaw materialDexamethasone base
Polyethylene Glycol
Benzyl alcohol
Ethanol
FillingFillingFillingFilling
OperationOperationOperationOperation
PackagingPackagingPackagingPackagingcomponentscomponentscomponentscomponentsGlass vials 10ml
Rubber stoppers
BulkBulkBulkBulk
manufacturingmanufacturingmanufacturingmanufacturing
Sterilization &Sterilization &Sterilization &Sterilization &Aseptic ProcessingAseptic ProcessingAseptic ProcessingAseptic Processing
Packaging &Packaging &Packaging &Packaging &
LabelingLabelingLabelingLabeling
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Raw materialsRaw materialsRaw materialsRaw materialsRaw materialsRaw materialsRaw materialsRaw materials
((((((((Processes involved)Processes involved)Processes involved)Processes involved)Processes involved)Processes involved)Processes involved)Processes involved)
• Selection & QualificationSelection & QualificationSelection & QualificationSelection & Qualification
• Set raw material specificationsSet raw material specificationsSet raw material specificationsSet raw material specifications• Supplier selection & auditSupplier selection & auditSupplier selection & auditSupplier selection & audit
• Routine testing & release of RMRoutine testing & release of RMRoutine testing & release of RMRoutine testing & release of RM
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Packaging componentsPackaging componentsPackaging componentsPackaging componentsPackaging componentsPackaging componentsPackaging componentsPackaging components(Processes involved)(Processes involved)(Processes involved)(Processes involved)(Processes involved)(Processes involved)(Processes involved)(Processes involved)
Glass vialsGlass vialsGlass vialsGlass vials
•Cleaning/washingCleaning/washingCleaning/washingCleaning/washing•Sterilization (dry heat)Sterilization (dry heat)Sterilization (dry heat)Sterilization (dry heat)
–Sterility assurance (10Sterility assurance (10Sterility assurance (10Sterility assurance (10––––6666))))
•DepyrogenationDepyrogenationDepyrogenationDepyrogenation
–Endotoxin reduction (10Endotoxin reduction (10Endotoxin reduction (10Endotoxin reduction (10––––3333))))
Rubber stoppersRubber stoppersRubber stoppersRubber stoppers
•Cleaning/washingCleaning/washingCleaning/washingCleaning/washing•SiliconizationSiliconizationSiliconizationSiliconization
•SterilizationSterilizationSterilizationSterilization
(Autoclaving)(Autoclaving)(Autoclaving)(Autoclaving)
– Sterility Assurance (10Sterility Assurance (10Sterility Assurance (10Sterility Assurance (10––––6666))))
•DepyrogenationDepyrogenationDepyrogenationDepyrogenation
– Endotoxin reduction (10Endotoxin reduction (10Endotoxin reduction (10Endotoxin reduction (10––––3333))))
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Bulk ManufacturingBulk ManufacturingBulk ManufacturingBulk ManufacturingBulk ManufacturingBulk ManufacturingBulk ManufacturingBulk Manufacturing
((((((((Processes involved)Processes involved)Processes involved)Processes involved)Processes involved)Processes involved)Processes involved)Processes involved)
• Bulk manufacturing processBulk manufacturing processBulk manufacturing processBulk manufacturing process
• Bulk bioBulk bioBulk bioBulk bio- -- -burden limitburden limitburden limitburden limit
• Bulk holding timeBulk holding timeBulk holding timeBulk holding time
• Bulk sterilization (Steam/Filtration)Bulk sterilization (Steam/Filtration)Bulk sterilization (Steam/Filtration)Bulk sterilization (Steam/Filtration)
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Filling OperationFilling OperationFilling OperationFilling OperationFilling OperationFilling OperationFilling OperationFilling Operation
((((((((Processes involved)Processes involved)Processes involved)Processes involved)Processes involved)Processes involved)Processes involved)Processes involved)
• CIP /SIP of the filling lineCIP /SIP of the filling lineCIP /SIP of the filling lineCIP /SIP of the filling line
• Filling processFilling processFilling processFilling process– Fill VolumeFill VolumeFill VolumeFill Volume
– Head spaceHead spaceHead spaceHead space
– ParticulatesParticulatesParticulatesParticulates
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Packaging operationPackaging operationPackaging operationPackaging operationPackaging operationPackaging operationPackaging operationPackaging operation
• Container/closure integrityContainer/closure integrityContainer/closure integrityContainer/closure integrity
– Dye ingressDye ingressDye ingressDye ingress
– Microbial ingressMicrobial ingressMicrobial ingressMicrobial ingress
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Labeling OperationLabeling OperationLabeling OperationLabeling OperationLabeling OperationLabeling OperationLabeling OperationLabeling Operation
• Label integrityLabel integrityLabel integrityLabel integrity
– Adherence strengthAdherence strengthAdherence strengthAdherence strength
– Printing ink strength & durabilityPrinting ink strength & durabilityPrinting ink strength & durabilityPrinting ink strength & durability
– Lot number & expiry dateLot number & expiry dateLot number & expiry dateLot number & expiry date
• Vision systemsVision systemsVision systemsVision systems
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Stability studiesStability studiesStability studiesStability studiesStability studiesStability studiesStability studiesStability studies• Broaching studyBroaching studyBroaching studyBroaching study
• Freeze /thaw studyFreeze /thaw studyFreeze /thaw studyFreeze /thaw study
• Photo stabilityPhoto stabilityPhoto stabilityPhoto stability
• Stress testingStress testingStress testingStress testing
- -- - Temperature stabilityTemperature stabilityTemperature stabilityTemperature stability
(Storage conditions)(Storage conditions)(Storage conditions)(Storage conditions)
- -- - Humidity requirementsHumidity requirementsHumidity requirementsHumidity requirements
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Shelf life & ExpiryShelf life & ExpiryShelf life & ExpiryShelf life & ExpiryShelf life & ExpiryShelf life & ExpiryShelf life & ExpiryShelf life & Expiry
• Accelerated studyAccelerated studyAccelerated studyAccelerated study
• Long term studyLong term studyLong term studyLong term study
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Not to mentionNot to mentionNot to mentionNot to mentionNot to mentionNot to mentionNot to mentionNot to mention
• Qualification (IQ/OQ/PQ) of all theQualification (IQ/OQ/PQ) of all theQualification (IQ/OQ/PQ) of all theQualification (IQ/OQ/PQ) of all the
manufacturing & testing equipmentmanufacturing & testing equipmentmanufacturing & testing equipmentmanufacturing & testing equipment
– Including calibrations & maintenanceIncluding calibrations & maintenanceIncluding calibrations & maintenanceIncluding calibrations & maintenance
• Validation of all the test methodsValidation of all the test methodsValidation of all the test methodsValidation of all the test methods
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All processes validatedAll processes validatedAll processes validatedAll processes validatedAll processes validatedAll processes validatedAll processes validatedAll processes validated
Is the Quality of the ProductIs the Quality of the ProductIs the Quality of the ProductIs the Quality of the ProductAssured?Assured?Assured?Assured?
All equipments qualifiedAll equipments qualifiedAll equipments qualifiedAll equipments qualifiedAll equipments qualifiedAll equipments qualifiedAll equipments qualifiedAll equipments qualifiedAll instruments calibratedAll instruments calibratedAll instruments calibratedAll instruments calibratedAll instruments calibratedAll instruments calibratedAll instruments calibratedAll instruments calibrated
All test methods validatedAll test methods validatedAll test methods validatedAll test methods validatedAll test methods validatedAll test methods validatedAll test methods validatedAll test methods validated
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No, it is not !No, it is not !No, it is not !No, it is not !No, it is not !No, it is not !No, it is not !No, it is not !• The initial qualification of the equipmentThe initial qualification of the equipmentThe initial qualification of the equipmentThe initial qualification of the equipment
& validation of the processes are only a& validation of the processes are only a& validation of the processes are only a& validation of the processes are only a
stamp at that moment in time on the lifestamp at that moment in time on the lifestamp at that moment in time on the lifestamp at that moment in time on the life
cycle of the products.cycle of the products.cycle of the products.cycle of the products.
• Assurance comes from the proof that allAssurance comes from the proof that allAssurance comes from the proof that allAssurance comes from the proof that all
equipments are maintained at the stateequipments are maintained at the stateequipments are maintained at the stateequipments are maintained at the state
they were qualified and all processes arethey were qualified and all processes arethey were qualified and all processes arethey were qualified and all processes are
regularly controlled in the validated state.regularly controlled in the validated state.regularly controlled in the validated state.regularly controlled in the validated state.
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Aseptic ProcessingAseptic ProcessingAseptic ProcessingAseptic ProcessingAseptic ProcessingAseptic ProcessingAseptic ProcessingAseptic Processing
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IntroductionIntroductionIntroductionIntroductionIntroductionIntroductionIntroductionIntroduction
Aseptic processing
The ability of personnel to manipulate
sterile preparations/products and sterilepackaging components in a way that
excludes the introduction of viable
microorganisms.
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How is aseptic processingHow is aseptic processingHow is aseptic processingHow is aseptic processingHow is aseptic processingHow is aseptic processingHow is aseptic processingHow is aseptic processingachieved?achieved?achieved?achieved?achieved?achieved?achieved?achieved?
•Development of CleanroomDevelopment of CleanroomDevelopment of CleanroomDevelopment of Cleanroom
environment & maintenanceenvironment & maintenanceenvironment & maintenanceenvironment & maintenance•Personnel that are qualified andPersonnel that are qualified andPersonnel that are qualified andPersonnel that are qualified and
trained in cleanroom operationtrained in cleanroom operationtrained in cleanroom operationtrained in cleanroom operation
•Validation of the processesValidation of the processesValidation of the processesValidation of the processes
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CleanroomCleanroomCleanroomCleanroomCleanroomCleanroomCleanroomCleanroom
DefinitionDefinitionDefinitionDefinition - -- -Room in which the concentration of airborne particles isRoom in which the concentration of airborne particles isRoom in which the concentration of airborne particles isRoom in which the concentration of airborne particles is
controlled, and which is constructed and used in acontrolled, and which is constructed and used in acontrolled, and which is constructed and used in acontrolled, and which is constructed and used in a
manner to minimize the introduction, generation, andmanner to minimize the introduction, generation, andmanner to minimize the introduction, generation, andmanner to minimize the introduction, generation, and
retention of particles inside the room, and in which otherretention of particles inside the room, and in which otherretention of particles inside the room, and in which otherretention of particles inside the room, and in which other
relevant parameters, e.g. temperature,humidity, andrelevant parameters, e.g. temperature,humidity, andrelevant parameters, e.g. temperature,humidity, andrelevant parameters, e.g. temperature,humidity, and
pressure, are controlled as necessarypressure, are controlled as necessarypressure, are controlled as necessarypressure, are controlled as necessary
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Cleanroom ClassificationCleanroom ClassificationCleanroom ClassificationCleanroom ClassificationCleanroom ClassificationCleanroom ClassificationCleanroom ClassificationCleanroom Classification cont . . .cont . . .cont . . .cont . . .cont . . .cont . . .cont . . .cont . . .
Technical Committee 209 of the International Organization forStandardization (ISO/TC209) has proposed the following eleven
(11) documents as the Clean room Standards:
ISO 14644-1: Classification of air cleanliness
ISO 14644-2: Cleanroom testing for Compliance
ISO 14644-3: Method for Evaluating & Measuring Cleanrooms &
Associated controlled environmentISO 14644-4: Cleanroom Design and Construction
ISO 14644-5: Cleanroom Operation
ISO 14644-6: Terms, Definition & Units
ISO 14644-7: Enhanced Clean Devices
ISO 14644-8: Molecular Contamination
ISO 14698-1: Bio-contamination: Control General PrinciplesISO 14698-2: Bio-contamination: Evaluation & Interpretation of Data
ISO 14698-3 Bio-contamination: Methodology for Measuring Efficiency of
Cleaning Inert Surfaces.
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Cleanroom ClassificationCleanroom ClassificationCleanroom ClassificationCleanroom ClassificationCleanroom ClassificationCleanroom ClassificationCleanroom ClassificationCleanroom ClassificationISO AIRBOURNE PARTICULATE CLEANLINESS CLASSES
Class Number of Particles per Cubic Meter
0.1 um 0.2 um 0.3 um 0.5 um 1 um 5 um
ISO 1 10 2 ¡¡ ¡¡ ¡¡ ¡¡
ISO 2 100 24 10 4 ¡¡ ¡¡
ISO 3 1,000 237 102 35 8 ¡¡
ISO 4 10,000 2,370 1,020 352 83 ¡¡
ISO 5 100,000 23,700 10,200 3,520 832 29
ISO 6 1,000,000237,000 102,000 35,200 8,320 293
ISO 7 ¡¡ ¡¡ ¡¡ 352,000 83,200 2,930
ISO 8 ¡¡ ¡¡ ¡¡ 3,520,000 832,000 29,300
ISO 9 ¡¡ ¡¡ ¡¡ 35,200,000 8,320,000 293,000
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Cleanroom designCleanroom designCleanroom designCleanroom design
The following to be consideredThe following to be consideredThe following to be consideredThe following to be considered
iCleanroom surfacesCleanroom surfacesCleanroom surfacesCleanroom surfaces
iCleanroom layoutCleanroom layoutCleanroom layoutCleanroom layout
iCleanroom equipmentCleanroom equipmentCleanroom equipmentCleanroom equipment
iClean Rooms ProceduresClean Rooms ProceduresClean Rooms ProceduresClean Rooms Procedures
iProduct issuesProduct issuesProduct issuesProduct issues
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Air Handling System (HVAC)Air Handling System (HVAC)Air Handling System (HVAC)Air Handling System (HVAC)Air Handling System (HVAC)Air Handling System (HVAC)Air Handling System (HVAC)Air Handling System (HVAC)
.
25% Outdoor Air Intake
through pre-filter 30-60%
75% Re-circulated Air
Heating /Cooling and
Dehumidification
Terminal HEPA Filter 99.97%
FAN MIXING BOX FAN
75-95% Pre-HEPA Filter
intermediate filter
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HEPA/ULPA filtersHEPA/ULPA filtersHEPA/ULPA filtersHEPA/ULPA filtersHEPA/ULPA filtersHEPA/ULPA filtersHEPA/ULPA filtersHEPA/ULPA filters
HEPA is an acronym forHEPA is an acronym forHEPA is an acronym forHEPA is an acronym for
‘High Efficiency Particulate Air’‘High Efficiency Particulate Air’‘High Efficiency Particulate Air’‘High Efficiency Particulate Air’
ULPA is an acronym forULPA is an acronym forULPA is an acronym forULPA is an acronym for
‘Ultra Low Penetration Air’‘Ultra Low Penetration Air’‘Ultra Low Penetration Air’‘Ultra Low Penetration Air’
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HEPA filtersHEPA filtersHEPA filtersHEPA filtersHEPA filtersHEPA filtersHEPA filtersHEPA filters• HEPA filtersHEPA filtersHEPA filtersHEPA filters are throwaway, extendedare throwaway, extendedare throwaway, extendedare throwaway, extended- -- -
medium, drymedium, drymedium, drymedium, dry- -- -type filter in a rigid frame havingtype filter in a rigid frame havingtype filter in a rigid frame havingtype filter in a rigid frame having
a minimum particlea minimum particlea minimum particlea minimum particle- -- -collection efficiency ofcollection efficiency ofcollection efficiency ofcollection efficiency of
99.97% for 0.399.97% for 0.399.97% for 0.399.97% for 0.3 µµµµm and larger, and am and larger, and am and larger, and am and larger, and amaximum cleanmaximum cleanmaximum cleanmaximum clean- -- -filter pressure drop of 2.54filter pressure drop of 2.54filter pressure drop of 2.54filter pressure drop of 2.54
cm water gauge (0.249 kPa), when tested atcm water gauge (0.249 kPa), when tested atcm water gauge (0.249 kPa), when tested atcm water gauge (0.249 kPa), when tested at
rated airflow capacity (85 L/min).rated airflow capacity (85 L/min).rated airflow capacity (85 L/min).rated airflow capacity (85 L/min).
- IES-RP-CC001, HEPA and ULPA Filters.
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ULPA filtersULPA filtersULPA filtersULPA filtersULPA filtersULPA filtersULPA filtersULPA filters
• ULPA filters are a throwaway, extendedULPA filters are a throwaway, extendedULPA filters are a throwaway, extendedULPA filters are a throwaway, extended- -- -
medium, drymedium, drymedium, drymedium, dry- -- -type filter in a rigid frame havingtype filter in a rigid frame havingtype filter in a rigid frame havingtype filter in a rigid frame having
a minimum particlea minimum particlea minimum particlea minimum particle- -- -collection efficiency ofcollection efficiency ofcollection efficiency ofcollection efficiency of99.999% for particles 0.12um and larger.99.999% for particles 0.12um and larger.99.999% for particles 0.12um and larger.99.999% for particles 0.12um and larger.
- IES-RP-CC001, HEPA and ULPA Filters.
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Cleanroom UtilitiesCleanroom UtilitiesCleanroom UtilitiesCleanroom UtilitiesCleanroom UtilitiesCleanroom UtilitiesCleanroom UtilitiesCleanroom Utilities
Cleanroom SteamCleanroom SteamCleanroom SteamCleanroom Steam
Plant SteamPlant SteamPlant SteamPlant Steam manufactured by boiler
using city water
Pure SteamPure SteamPure SteamPure Steam manufactured by steamgenerator using purified water
WaterWaterWaterWater
Compressed AirCompressed AirCompressed AirCompressed Air
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Cleanroom CertificationCleanroom CertificationCleanroom CertificationCleanroom CertificationCleanroom CertificationCleanroom CertificationCleanroom CertificationCleanroom Certification
ISO 14664ISO 14664ISO 14664ISO 14664- -- -2:2000(E): Specifications for testing and2:2000(E): Specifications for testing and2:2000(E): Specifications for testing and2:2000(E): Specifications for testing and
monitoring to prove continued compliance with ISOmonitoring to prove continued compliance with ISOmonitoring to prove continued compliance with ISOmonitoring to prove continued compliance with ISO
14644146441464414644- -- -1111
Normative TestiAirborne Particle Count (cleanroom classification)Airborne Particle Count (cleanroom classification)Airborne Particle Count (cleanroom classification)Airborne Particle Count (cleanroom classification)
iAirflow Velocity / Air Volume TestsAirflow Velocity / Air Volume TestsAirflow Velocity / Air Volume TestsAirflow Velocity / Air Volume Tests
iRoom Pressure Differential TestRoom Pressure Differential TestRoom Pressure Differential TestRoom Pressure Differential Test
Optional Tests in Annex AiHEPA filter installation leak (integrity) testsHEPA filter installation leak (integrity) testsHEPA filter installation leak (integrity) testsHEPA filter installation leak (integrity) tests
iAirflow visualization (smoke video)Airflow visualization (smoke video)Airflow visualization (smoke video)Airflow visualization (smoke video)
iRecoveryRecoveryRecoveryRecovery
iContainment LeakageContainment LeakageContainment LeakageContainment Leakage
Other TestsOther TestsOther TestsOther Tests - -- - Temperature, Humidity, Light and Noise LevelTemperature, Humidity, Light and Noise LevelTemperature, Humidity, Light and Noise LevelTemperature, Humidity, Light and Noise Level
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Cleanroom CertificationCleanroom CertificationCleanroom CertificationCleanroom CertificationCleanroom CertificationCleanroom CertificationCleanroom CertificationCleanroom Certification
HEPA Filter Leak (Integrity) TestingHEPA Filter Leak (Integrity) TestingHEPA Filter Leak (Integrity) TestingHEPA Filter Leak (Integrity) Testing
These tests are performed to confirm that the HEPA orThese tests are performed to confirm that the HEPA orThese tests are performed to confirm that the HEPA orThese tests are performed to confirm that the HEPA or
ULPA filter system is properly installed by verifying theULPA filter system is properly installed by verifying theULPA filter system is properly installed by verifying theULPA filter system is properly installed by verifying the
absence of bypass leakage in the installation, and that theabsence of bypass leakage in the installation, and that theabsence of bypass leakage in the installation, and that theabsence of bypass leakage in the installation, and that the
filters are free of defects and small leaks. The tests arefilters are free of defects and small leaks. The tests arefilters are free of defects and small leaks. The tests arefilters are free of defects and small leaks. The tests are
particularly important for cleanrooms and clean zonesparticularly important for cleanrooms and clean zonesparticularly important for cleanrooms and clean zonesparticularly important for cleanrooms and clean zones
classified atclassified atclassified atclassified at
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Cleanroom CertificationCleanroom CertificationCleanroom CertificationCleanroom CertificationCleanroom CertificationCleanroom CertificationCleanroom CertificationCleanroom Certification
HEPA Filter Leak (Integrity) TestingHEPA Filter Leak (Integrity) TestingHEPA Filter Leak (Integrity) TestingHEPA Filter Leak (Integrity) Testing
ResultsResultsResultsResults
i The leaks
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Cleanroom CertificationCleanroom CertificationCleanroom CertificationCleanroom CertificationCleanroom CertificationCleanroom CertificationCleanroom CertificationCleanroom Certification
Air Flow Velocity/VolumeAir Flow Velocity/VolumeAir Flow Velocity/VolumeAir Flow Velocity/Volume
Normally a air velocity of 90 ft/minNormally a air velocity of 90 ft/minNormally a air velocity of 90 ft/minNormally a air velocity of 90 ft/min
± 20% is adequate.± 20% is adequate.± 20% is adequate.± 20% is adequate.
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Cleanroom CertificationCleanroom CertificationCleanroom CertificationCleanroom CertificationCleanroom CertificationCleanroom CertificationCleanroom CertificationCleanroom Certification
Air ChangesAir ChangesAir ChangesAir Changes
The air changes can be calculated by taking the totalThe air changes can be calculated by taking the totalThe air changes can be calculated by taking the totalThe air changes can be calculated by taking the total
volumes divided by room volume and reported as airvolumes divided by room volume and reported as airvolumes divided by room volume and reported as airvolumes divided by room volume and reported as air
changes per hr.changes per hr.changes per hr.changes per hr.
Not less then 20 air changes per hour are acceptable.Not less then 20 air changes per hour are acceptable.Not less then 20 air changes per hour are acceptable.Not less then 20 air changes per hour are acceptable.
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Cleanroom CertificationCleanroom CertificationCleanroom CertificationCleanroom CertificationCleanroom CertificationCleanroom CertificationCleanroom CertificationCleanroom Certification
Air Pressure DifferentialAir Pressure DifferentialAir Pressure DifferentialAir Pressure Differential
Acceptance criteriaAcceptance criteriaAcceptance criteriaAcceptance criteria
- A pressure differential of at least 0.05A pressure differential of at least 0.05A pressure differential of at least 0.05A pressure differential of at least 0.05inch of water (with all door closed)inch of water (with all door closed)inch of water (with all door closed)inch of water (with all door closed)
relative to adjacent area is acceptablerelative to adjacent area is acceptablerelative to adjacent area is acceptablerelative to adjacent area is acceptable
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Cleanroom CertificationCleanroom CertificationCleanroom CertificationCleanroom CertificationCleanroom CertificationCleanroom CertificationCleanroom CertificationCleanroom Certification
Air Flow VisualizationAir Flow VisualizationAir Flow VisualizationAir Flow Visualization (Smoke TestingSmoke TestingSmoke TestingSmoke Testing)
Performed in order to assure thatPerformed in order to assure thatPerformed in order to assure thatPerformed in order to assure that
ithe unidirectional flow of HEPA filtered air is notthe unidirectional flow of HEPA filtered air is notthe unidirectional flow of HEPA filtered air is notthe unidirectional flow of HEPA filtered air is not
compromisedcompromisedcompromisedcompromised
ithe air moves in a downward direction awaythe air moves in a downward direction awaythe air moves in a downward direction awaythe air moves in a downward direction away
from the work surfacesfrom the work surfacesfrom the work surfacesfrom the work surfaces
iAir flow patterns don’t present a contaminationAir flow patterns don’t present a contaminationAir flow patterns don’t present a contaminationAir flow patterns don’t present a contamination
riskriskriskriskito detect dead spotsto detect dead spotsto detect dead spotsto detect dead spots
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Cleanroom CertificationCleanroom CertificationCleanroom CertificationCleanroom CertificationCleanroom CertificationCleanroom CertificationCleanroom CertificationCleanroom Certification
Airborne Particle CountsAirborne Particle CountsAirborne Particle CountsAirborne Particle Counts
Acceptance for Airborne Particle CountsAcceptance for Airborne Particle CountsAcceptance for Airborne Particle CountsAcceptance for Airborne Particle Counts
iThe average particle concentration at eachThe average particle concentration at eachThe average particle concentration at eachThe average particle concentration at each
sample location should fall below the classsample location should fall below the classsample location should fall below the classsample location should fall below the classlimitlimitlimitlimit
iThe mean of of these averages should fallThe mean of of these averages should fallThe mean of of these averages should fallThe mean of of these averages should fall
at or below the class limit with 95% upperat or below the class limit with 95% upperat or below the class limit with 95% upperat or below the class limit with 95% upper
confidence level (UCL)confidence level (UCL)confidence level (UCL)confidence level (UCL)
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Microbial controlMicrobial controlMicrobial controlMicrobial control
Environmental Monitoring ProgramEnvironmental Monitoring ProgramEnvironmental Monitoring ProgramEnvironmental Monitoring Program
hEstablishment of Sampling Plan & SiteEstablishment of Sampling Plan & SiteEstablishment of Sampling Plan & SiteEstablishment of Sampling Plan & Site
hTesting MethodsTesting MethodsTesting MethodsTesting Methods
hTesting DevicesTesting DevicesTesting DevicesTesting Devices
hTesting FrequenciesTesting FrequenciesTesting FrequenciesTesting Frequencies
hAction / Alert LimitsAction / Alert LimitsAction / Alert LimitsAction / Alert Limits
hFollow Up & IdentificationFollow Up & IdentificationFollow Up & IdentificationFollow Up & Identification
Cleanroom EnvironmentCleanroom Environment
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Environmental MonitoringEnvironmental MonitoringEnvironmental MonitoringEnvironmental MonitoringEnvironmental MonitoringEnvironmental MonitoringEnvironmental MonitoringEnvironmental Monitoring
ProgramProgramProgramProgramProgramProgramProgramProgram
A program capable of detecting anA program capable of detecting anA program capable of detecting anA program capable of detecting an
adverse drift in microbiologicaladverse drift in microbiologicaladverse drift in microbiologicaladverse drift in microbiological
conditions in a timely manner andconditions in a timely manner andconditions in a timely manner andconditions in a timely manner andwould allow for meaningful andwould allow for meaningful andwould allow for meaningful andwould allow for meaningful and
effective corrective actions.effective corrective actions.effective corrective actions.effective corrective actions.
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Environmental MonitoringEnvironmental MonitoringEnvironmental MonitoringEnvironmental MonitoringEnvironmental MonitoringEnvironmental MonitoringEnvironmental MonitoringEnvironmental Monitoring
•Testing MethodsTesting MethodsTesting MethodsTesting Methods
•Testing FrequencyTesting FrequencyTesting FrequencyTesting Frequency
•Setting of Alert & Action limitSetting of Alert & Action limitSetting of Alert & Action limitSetting of Alert & Action limit
•Microbial IdentificationMicrobial IdentificationMicrobial IdentificationMicrobial Identification•DeviationsDeviationsDeviationsDeviations
•FollowFollowFollowFollow- -- -Up & Corrective ActionUp & Corrective ActionUp & Corrective ActionUp & Corrective Action
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Validation of Aseptic ProcessingValidation of Aseptic ProcessingValidation of Aseptic ProcessingValidation of Aseptic ProcessingValidation of Aseptic ProcessingValidation of Aseptic ProcessingValidation of Aseptic ProcessingValidation of Aseptic Processing
Involves all of the followingInvolves all of the followingInvolves all of the followingInvolves all of the following ––––• Qualification & Maintenance of well designed HVAC systemQualification & Maintenance of well designed HVAC systemQualification & Maintenance of well designed HVAC systemQualification & Maintenance of well designed HVAC system
• Initial & periodic Certification of Cleanrooms & HEPA filtersInitial & periodic Certification of Cleanrooms & HEPA filtersInitial & periodic Certification of Cleanrooms & HEPA filtersInitial & periodic Certification of Cleanrooms & HEPA filters
• Validated Cleaning & Sanitization proceduresValidated Cleaning & Sanitization proceduresValidated Cleaning & Sanitization proceduresValidated Cleaning & Sanitization procedures
• Validated sterilization of Bulk & Packaging ComponentsValidated sterilization of Bulk & Packaging ComponentsValidated sterilization of Bulk & Packaging ComponentsValidated sterilization of Bulk & Packaging Components• Validated state of Utility systems (Water, Comp. Air etc.)Validated state of Utility systems (Water, Comp. Air etc.)Validated state of Utility systems (Water, Comp. Air etc.)Validated state of Utility systems (Water, Comp. Air etc.)
• Maintaining trained & qualified cleanroom personnelMaintaining trained & qualified cleanroom personnelMaintaining trained & qualified cleanroom personnelMaintaining trained & qualified cleanroom personnel
• Good record of environmental monitoring & trending.Good record of environmental monitoring & trending.Good record of environmental monitoring & trending.Good record of environmental monitoring & trending.
• An excellent track record of Investigations & CAPA system.An excellent track record of Investigations & CAPA system.An excellent track record of Investigations & CAPA system.An excellent track record of Investigations & CAPA system.
• Process Simulation (Media fills)Process Simulation (Media fills)Process Simulation (Media fills)Process Simulation (Media fills)
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Process Simulation (Media fills)Process Simulation (Media fills)Process Simulation (Media fills)Process Simulation (Media fills)Process Simulation (Media fills)Process Simulation (Media fills)Process Simulation (Media fills)Process Simulation (Media fills)
ObjectiveObjectiveObjectiveObjective
The intent of a process simulation study is toThe intent of a process simulation study is toThe intent of a process simulation study is toThe intent of a process simulation study is todemonstrate that the aseptic processingdemonstrate that the aseptic processingdemonstrate that the aseptic processingdemonstrate that the aseptic processing
employed for the manufacturing of sterileemployed for the manufacturing of sterileemployed for the manufacturing of sterileemployed for the manufacturing of sterile
products, with its day to day normal activitiesproducts, with its day to day normal activitiesproducts, with its day to day normal activitiesproducts, with its day to day normal activitiesand interventions, does indeed result in aand interventions, does indeed result in aand interventions, does indeed result in aand interventions, does indeed result in a
sterile product.sterile product.sterile product.sterile product.
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Process Simulation (Media fills)Process Simulation (Media fills)Process Simulation (Media fills)Process Simulation (Media fills)Process Simulation (Media fills)Process Simulation (Media fills)Process Simulation (Media fills)Process Simulation (Media fills)
The media fill collectively evaluates theThe media fill collectively evaluates theThe media fill collectively evaluates theThe media fill collectively evaluates the
adequacy of the following:adequacy of the following:adequacy of the following:adequacy of the following:
i Disinfecting TechniquesDisinfecting TechniquesDisinfecting TechniquesDisinfecting Techniques
i Transfer of sterile materialTransfer of sterile materialTransfer of sterile materialTransfer of sterile material
i Training of personnelTraining of personnelTraining of personnelTraining of personnel
i Cleanroom Environmental ControlCleanroom Environmental ControlCleanroom Environmental ControlCleanroom Environmental Control
i Aseptic assemblyAseptic assemblyAseptic assemblyAseptic assembly
i Aseptic techniques & behaviorAseptic techniques & behaviorAseptic techniques & behaviorAseptic techniques & behavior
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Process Simulation (Media fills)Process Simulation (Media fills)Process Simulation (Media fills)Process Simulation (Media fills)Process Simulation (Media fills)Process Simulation (Media fills)Process Simulation (Media fills)Process Simulation (Media fills)
iInitial ValidationInitial ValidationInitial ValidationInitial Validation
Minimum of three consecutive successfulMinimum of three consecutive successfulMinimum of three consecutive successfulMinimum of three consecutive successful
runsrunsrunsruns
iRoutine reRoutine reRoutine reRoutine re- -- -validationvalidationvalidationvalidation
iMinimum reMinimum reMinimum reMinimum re- -- -test frequency should be twice pertest frequency should be twice pertest frequency should be twice pertest frequency should be twice per
year per operator shift or team, for each processyear per operator shift or team, for each processyear per operator shift or team, for each processyear per operator shift or team, for each process
line.line.line.line.
iEvery 6 months (FDA Draft & ISO13408Every 6 months (FDA Draft & ISO13408Every 6 months (FDA Draft & ISO13408Every 6 months (FDA Draft & ISO13408- -- -1)1)1)1)
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Process Simulation (Media fills)Process Simulation (Media fills)Process Simulation (Media fills)Process Simulation (Media fills)Process Simulation (Media fills)Process Simulation (Media fills)Process Simulation (Media fills)Process Simulation (Media fills)
Planned InterventionsPlanned InterventionsPlanned InterventionsPlanned Interventions performed during MF
Worse case interventionsWorse case interventionsWorse case interventionsWorse case interventions
• Clean up of spillClean up of spillClean up of spillClean up of spill
• Simulation of mechanical adjustment, stoppages or transferSimulation of mechanical adjustment, stoppages or transferSimulation of mechanical adjustment, stoppages or transferSimulation of mechanical adjustment, stoppages or transfer
• Long storage of components in the hoppersLong storage of components in the hoppersLong storage of components in the hoppersLong storage of components in the hoppers
• Including multiple shifts or maximum hrs of continuousIncluding multiple shifts or maximum hrs of continuousIncluding multiple shifts or maximum hrs of continuousIncluding multiple shifts or maximum hrs of continuous
processingprocessingprocessingprocessing
• Consideration of temperature and humidity set point extremesConsideration of temperature and humidity set point extremesConsideration of temperature and humidity set point extremesConsideration of temperature and humidity set point extremes
• Maximum number of operators and their activitiesMaximum number of operators and their activitiesMaximum number of operators and their activitiesMaximum number of operators and their activities
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Process Simulation (Media fills)Process Simulation (Media fills)Process Simulation (Media fills)Process Simulation (Media fills)Process Simulation (Media fills)Process Simulation (Media fills)Process Simulation (Media fills)Process Simulation (Media fills)
Number of units to be filled
The number of units filled should be relevant to productionThe number of units filled should be relevant to productionThe number of units filled should be relevant to productionThe number of units filled should be relevant to production
batch size which allowed to detect a 0.1% contaminationbatch size which allowed to detect a 0.1% contaminationbatch size which allowed to detect a 0.1% contaminationbatch size which allowed to detect a 0.1% contamination
with 95% CLwith 95% CLwith 95% CLwith 95% CL
For small batch sizes, the number of units filled should beFor small batch sizes, the number of units filled should beFor small batch sizes, the number of units filled should beFor small batch sizes, the number of units filled should be
actual batch size with no positiveactual batch size with no positiveactual batch size with no positiveactual batch size with no positive
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Volume to be filled
the volume should be normal production fill volumethe volume should be normal production fill volumethe volume should be normal production fill volumethe volume should be normal production fill volume
where possible. In the case of high volume containers,where possible. In the case of high volume containers,where possible. In the case of high volume containers,where possible. In the case of high volume containers,
a lesser quantity may be used, provided the steps area lesser quantity may be used, provided the steps area lesser quantity may be used, provided the steps area lesser quantity may be used, provided the steps are
taken to ensure wetting of all the inner surfaces of thetaken to ensure wetting of all the inner surfaces of thetaken to ensure wetting of all the inner surfaces of thetaken to ensure wetting of all the inner surfaces of thecontainer and any closure, by the mediumcontainer and any closure, by the mediumcontainer and any closure, by the mediumcontainer and any closure, by the medium
The fill volume of TSBThe fill volume of TSBThe fill volume of TSBThe fill volume of TSB - -- - filled unit during incubationfilled unit during incubationfilled unit during incubationfilled unit during incubation
must be large enough to facilitate growth ofmust be large enough to facilitate growth ofmust be large enough to facilitate growth ofmust be large enough to facilitate growth of
microorganisms.microorganisms.microorganisms.microorganisms.
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Process Simulation (Media fills)Process Simulation (Media fills)Process Simulation (Media fills)Process Simulation (Media fills)Process Simulation (Media fills)Process Simulation (Media fills)Process Simulation (Media fills)Process Simulation (Media fills)
Media Fill RejectsMedia Fill RejectsMedia Fill RejectsMedia Fill RejectsAll units filled should be incubated (including cosmeticsAll units filled should be incubated (including cosmeticsAll units filled should be incubated (including cosmeticsAll units filled should be incubated (including cosmetics
rejects i.e. low volume, black spec) with the exception ofrejects i.e. low volume, black spec) with the exception ofrejects i.e. low volume, black spec) with the exception ofrejects i.e. low volume, black spec) with the exception of
leakers or potential leakersleakers or potential leakersleakers or potential leakersleakers or potential leakers
• Crooked caps,Crooked caps,Crooked caps,Crooked caps,
• Cracked vials or capsCracked vials or capsCracked vials or capsCracked vials or caps• Low torqueLow torqueLow torqueLow torque
• deformed containerdeformed containerdeformed containerdeformed container
• Units failed onUnits failed onUnits failed onUnits failed on- -- -line leak testline leak testline leak testline leak test
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Process Simulation (Media fills)Process Simulation (Media fills)Process Simulation (Media fills)Process Simulation (Media fills)Process Simulation (Media fills)Process Simulation (Media fills)Process Simulation (Media fills)Process Simulation (Media fills)
InInInIn- -- -process microbiological monitoringprocess microbiological monitoringprocess microbiological monitoringprocess microbiological monitoring
iOperators’ qualification (glove /gown testing)Operators’ qualification (glove /gown testing)Operators’ qualification (glove /gown testing)Operators’ qualification (glove /gown testing)
iSurface monitoring (pre & post media Fill)Surface monitoring (pre & post media Fill)Surface monitoring (pre & post media Fill)Surface monitoring (pre & post media Fill)
iQuantitative Air sampling (before & duringQuantitative Air sampling (before & duringQuantitative Air sampling (before & duringQuantitative Air sampling (before & duringmedia fill)media fill)media fill)media fill)
iSettling Plate monitoringSettling Plate monitoringSettling Plate monitoringSettling Plate monitoring
iParticulate monitoringParticulate monitoringParticulate monitoringParticulate monitoring
iMicrobial identificationMicrobial identificationMicrobial identificationMicrobial identification
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Acceptance CriteriaAcceptance CriteriaAcceptance CriteriaAcceptance Criteria
1.1.1.1. Media Growth PromotionMedia Growth PromotionMedia Growth PromotionMedia Growth Promotion
i the prepared bulk media should be clear so as to allowthe prepared bulk media should be clear so as to allowthe prepared bulk media should be clear so as to allowthe prepared bulk media should be clear so as to allow
the observation of any evidence of growth followingthe observation of any evidence of growth followingthe observation of any evidence of growth followingthe observation of any evidence of growth followingincubation.incubation.incubation.incubation.
i media used in evaluation must pass the USP growthmedia used in evaluation must pass the USP growthmedia used in evaluation must pass the USP growthmedia used in evaluation must pass the USP growth
promotion test where a challenge with between 10promotion test where a challenge with between 10promotion test where a challenge with between 10promotion test where a challenge with between 10- -- -100100100100
organism per container must show the growthorganism per container must show the growthorganism per container must show the growthorganism per container must show the growth
characteristics of the organismcharacteristics of the organismcharacteristics of the organismcharacteristics of the organism
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Acceptance CriteriaAcceptance CriteriaAcceptance CriteriaAcceptance Criteria“Any contaminated units should be considered objectionable“Any contaminated units should be considered objectionable“Any contaminated units should be considered objectionable“Any contaminated units should be considered objectionable
and investigated”and investigated”and investigated”and investigated”
2.2.2.2. Recommended criteria for state of control are as follows:Recommended criteria for state of control are as follows:Recommended criteria for state of control are as follows:Recommended criteria for state of control are as follows:
i For < 5,000 units filledFor < 5,000 units filledFor < 5,000 units filledFor < 5,000 units filled –––– No contaminated units.No contaminated units.No contaminated units.No contaminated units.
One contaminated unitOne contaminated unitOne contaminated unitOne contaminated unit –––– Investigation & RevalidationInvestigation & RevalidationInvestigation & RevalidationInvestigation & Revalidation
i For 5,000 to 10,000 units filledFor 5,000 to 10,000 units filledFor 5,000 to 10,000 units filledFor 5,000 to 10,000 units filled - -- -
One contaminated unitOne contaminated unitOne contaminated unitOne contaminated unit –––– Investigation & consideration forInvestigation & consideration forInvestigation & consideration forInvestigation & consideration for
RevalidationRevalidationRevalidationRevalidation
Two contaminated unitsTwo contaminated unitsTwo contaminated unitsTwo contaminated units - -- - Investigation & RevalidationInvestigation & RevalidationInvestigation & RevalidationInvestigation & Revalidation
i For > 10,000 units filledFor > 10,000 units filledFor > 10,000 units filledFor > 10,000 units filled - -- -One contaminated unitOne contaminated unitOne contaminated unitOne contaminated unit –––– InvestigationInvestigationInvestigationInvestigation
Two contaminated unitsTwo contaminated unitsTwo contaminated unitsTwo contaminated units - -- - Investigation & RevalidationInvestigation & RevalidationInvestigation & RevalidationInvestigation & Revalidation
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Process Simulation (Media fills)Process Simulation (Media fills)Process Simulation (Media fills)Process Simulation (Media fills)Process Simulation (Media fills)Process Simulation (Media fills)Process Simulation (Media fills)Process Simulation (Media fills)
Invalidation of Media fillInvalidation of Media fillInvalidation of Media fillInvalidation of Media fill
In validation of a media fill run should be aIn validation of a media fill run should be aIn validation of a media fill run should be aIn validation of a media fill run should be a
rare occurrencerare occurrencerare occurrencerare occurrence
A media fill run should be aborted only underA media fill run should be aborted only underA media fill run should be aborted only underA media fill run should be aborted only under
circumstances in which written procedurescircumstances in which written procedurescircumstances in which written procedurescircumstances in which written procedures
require commercial to be equally handledrequire commercial to be equally handledrequire commercial to be equally handledrequire commercial to be equally handled
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Process Simulation (Media fills)Process Simulation (Media fills)Process Simulation (Media fills)Process Simulation (Media fills)Process Simulation (Media fills)Process Simulation (Media fills)Process Simulation (Media fills)Process Simulation (Media fills)
RevalidationRevalidationRevalidationRevalidation
If an assign able cause is found for a processIf an assign able cause is found for a processIf an assign able cause is found for a processIf an assign able cause is found for a process
or area, only one process simulation isor area, only one process simulation isor area, only one process simulation isor area, only one process simulation is
required for rerequired for rerequired for rerequired for re- -- -qualification after correctingqualification after correctingqualification after correctingqualification after correctingthe causethe causethe causethe cause
If no root cause is found for processIf no root cause is found for processIf no root cause is found for processIf no root cause is found for process
simulation failure, three consecutivesimulation failure, three consecutivesimulation failure, three consecutivesimulation failure, three consecutive
successful process simulation runs required.successful process simulation runs required.successful process simulation runs required.successful process simulation runs required.
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RevalidationRevalidationRevalidationRevalidation
Repeat media fill must use the same equipment,Repeat media fill must use the same equipment,Repeat media fill must use the same equipment,Repeat media fill must use the same equipment,
same operators, same line, same process,same operators, same line, same process,same operators, same line, same process,same operators, same line, same process,
container /closures, same interventions with thecontainer /closures, same interventions with thecontainer /closures, same interventions with thecontainer /closures, same interventions with the
exception of correcting the root cause.exception of correcting the root cause.exception of correcting the root cause.exception of correcting the root cause.
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??
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Thank you Thank you Thank you Thank you Thank you Thank you Thank you Thank you