CVG Aseptic Processing Read Only

8/19/2019 CVG Aseptic Processing Read Only

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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


• 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


• 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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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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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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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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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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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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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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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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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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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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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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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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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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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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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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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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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

CVG Aseptic Processing Read Only

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