ASEPTIC PROCESSING OPERATION

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What is Aseptic Processing?What is Aseptic Processing?

The production of sterile drug products by bringing together The production of sterile drug products by bringing together the product, container, and closure that have been subjected to the product, container, and closure that have been subjected to different sterilization methods separately, and assembled them different sterilization methods separately, and assembled them in an extremely high quality environment by skilled personnel in an extremely high quality environment by skilled personnel using the right tools.using the right tools.

Aseptic Processing: Essential ElementsAseptic Processing: Essential Elements

Docume-ntation

Finish Product

Testing

Control &Verification

Personnel

Process

Equipment

Facility

Aseptic Processing

Aseptic Processing: Essential ElementsAseptic Processing: Essential Elements

FacilityFacility– DesignDesign

Zoning, Differential PressureZoning, Differential Pressure Temperature Temperature Relative HumidityRelative Humidity Personnel and Material FlowPersonnel and Material Flow

– Air FiltrationAir Filtration EquipmentEquipment

– Material of ConstructionMaterial of Construction– SanitizationSanitization– Component Preparation/SterilizationComponent Preparation/Sterilization

Aseptic Processing: Essential ElementsAseptic Processing: Essential Elements

ProcessProcess– Product FormulationProduct Formulation– FiltrationFiltration– FillingFilling– LyophilizationLyophilization– CappingCapping

PersonnelPersonnel– Gowning QualificationGowning Qualification– Aseptic TechniqueAseptic Technique

Control and VerificationControl and Verification– Environmental and Personnel MonitoringEnvironmental and Personnel Monitoring– Aseptic Filling Simulations (Media Fills)Aseptic Filling Simulations (Media Fills)

Aseptic Processing: Essential ElementsAseptic Processing: Essential Elements

Finished Product TestingFinished Product Testing– Sterility TestingSterility Testing– Particulate TestingParticulate Testing– Container Closure Integrity TestingContainer Closure Integrity Testing– Other Final Product/Release TestingOther Final Product/Release Testing– Stability TestingStability Testing

DocumentationDocumentation– Media Fill RecordsMedia Fill Records– Production Batch RecordsProduction Batch Records– EM Trend DataEM Trend Data– Release Testing Batch RecordsRelease Testing Batch Records– InvestigationInvestigation

Response to ExcursionsResponse to Excursions Corrective ActionsCorrective Actions

Environmental Monitoring ComponentsEnvironmental Monitoring Components

Airborne nonviable particulate monitoringAirborne nonviable particulate monitoring Airborne viable contaminant monitoringAirborne viable contaminant monitoring Viable contaminant monitoring of surfacesViable contaminant monitoring of surfaces Viable contaminant monitoring of personnelViable contaminant monitoring of personnel Temperature and humidity monitoringTemperature and humidity monitoring Pressure differential monitoringPressure differential monitoring

Environmental Monitoring ComponentsEnvironmental Monitoring Components

Water monitoring:Water monitoring:

– Total organic carbonTotal organic carbon– ConductivityConductivity– Microbial ContaminantsMicrobial Contaminants– EndotoxinEndotoxin

Air monitoring:Air monitoring:– Microbial Contaminants.Microbial Contaminants.

Regulatory Basis for Environmental Monitoring Regulatory Basis for Environmental Monitoring ProgramProgram

CFR GMP regulationsCFR GMP regulations FDA Guidance DocumentsFDA Guidance Documents USP Informational ChapterUSP Informational Chapter

Controlled AreaControlled Area

Preparation or manufacturing area where nonsterile product, Preparation or manufacturing area where nonsterile product, in-process materials and product-contact equipment surfaces, in-process materials and product-contact equipment surfaces, containers and closures are exposed to the environmentcontainers and closures are exposed to the environment

Control nonviable and viable contaminants to reduce Control nonviable and viable contaminants to reduce product /process bioburdenproduct /process bioburden

Class 100,000 or Class 10,000Class 100,000 or Class 10,000 Capping areas are now considered controlled manufacturing Capping areas are now considered controlled manufacturing

areasareas

– Should be supplied with HEPA filtered airShould be supplied with HEPA filtered air

– Should meet class 100,000 conditions during static Should meet class 100,000 conditions during static conditions conditions

Critical AreaCritical Area

Aseptic processing area where sterile products, components or Aseptic processing area where sterile products, components or in-process products are exposed to the environment and no in-process products are exposed to the environment and no further processing will occur.further processing will occur.

Air quality must be Class 100 during processingAir quality must be Class 100 during processing Local Class 100 areas are often utilized during open Local Class 100 areas are often utilized during open

processing steps during drug substance manufacture.processing steps during drug substance manufacture.

• The area just preceding the sterile core should be one classification higher than the core.

Types of waterTypes of water used in pharmaceutical processes used in pharmaceutical processes

1.1. Purified waterPurified water

2.2. Water for InjectionWater for Injections – PFW & WFIs – PFW & WFI

3.3. Softened WaterSoftened Water

4.4. Water for Final RinseWater for Final Rinse

5.5. Pure, or clean SteamPure, or clean Steam

6.6. WaterWater for cooling Autoclaves for cooling Autoclaves

Microbial testing of air and water

Why purify raw waterWhy purify raw water??

1.1. Although reasonably pure, Although reasonably pure, it is it is always variablealways variable

2.2. Seasonal variations may occurSeasonal variations may occur in water in water

3.3. Some regions have very poor qualitySome regions have very poor quality water water

4.4. Must remove impuritiesMust remove impurities to prevent product to prevent product contamination.contamination.

5.5. ControlControl microbesmicrobes to to avoid contaminating productsavoid contaminating products

Contaminants of water (1)Contaminants of water (1) There is nThere is no pure water in natureo pure water in nature, as it can contain up to , as it can contain up to 90 90

possible unacceptable contaminantspossible unacceptable contaminants

Contaminant groups:Contaminant groups:1.1. IInorganicnorganic compounds compounds2.2. OrOrgagannic compoundsic compounds3.3. Solids Solids 4.4. GasesGases5.5. Micro-organismsMicro-organisms

Contaminants of water (Contaminants of water (22))

Micro-organisms Micro-organisms ::1.1. AlgaeAlgae2.2. ProtozoaProtozoa

– CryptosporidiumCryptosporidium– GiardiaGiardia

3.3. BacteriaBacteria– PseudomonasPseudomonas– Gram negative, non-fermenting bacteriaGram negative, non-fermenting bacteria– Escherichia coli and coli formsEscherichia coli and coli forms

Contaminants of water (3)Contaminants of water (3)

Treatment depends on water’s chemistry and contaminants, Treatment depends on water’s chemistry and contaminants, influencedinfluenced by by::1.1. RainfallRainfall2.2. Erosion Erosion 3.3. PollutionPollution 4.4. DissolutionDissolution5.5. EvaporationEvaporation6.6. SedimentationSedimentation7.7. DecompositionDecomposition

Contaminants of water (4)Contaminants of water (4)

Problem mProblem mineralsinerals

1.1. Calcium and magnesium Calcium and magnesium

2.2. Iron and manganeseIron and manganese

3.3. SilicatesSilicates

4.4. Carbon dioxideCarbon dioxide

5.5. Hydrogen sulfideHydrogen sulfide

6.6. PhosphatesPhosphates

Contaminants of water (Contaminants of water (55))

Further problem mineralsFurther problem minerals 1.1. CopperCopper2.2. AluminumAluminum3.3. Heavy metalsHeavy metals

– Arsenic, lead, cadmiumArsenic, lead, cadmium4.4. NitratesNitrates

Water For InjectionWater For Injection

Defined by USPDefined by USP Water purified by distillation or reverse osmosisWater purified by distillation or reverse osmosis Prepared from water complying with the U.S. EPA National Prepared from water complying with the U.S. EPA National

Primary Drinking Water RegulationsPrimary Drinking Water Regulations Contains no added substanceContains no added substance

Purified WaterPurified Water

Defined in USPDefined in USP Obtained by a suitable process, usually one of the following:Obtained by a suitable process, usually one of the following:

– deionizationdeionization

– reverse osmosisreverse osmosis

– combinationcombination

Potable WaterPotable Water

Meets National Drinking Water RegulationsMeets National Drinking Water Regulations 40 CFR Part 14140 CFR Part 141 Periodic monitoring in-house as well as periodic certificates Periodic monitoring in-house as well as periodic certificates

from municipality (if applicable)from municipality (if applicable)

Microbiological TestingMicrobiological Testing

ObjectivesObjectives To review microbiological environmental and quality To review microbiological environmental and quality

control testingcontrol testing– Microbiological Environmental MonitoringMicrobiological Environmental Monitoring– Container integrity testingContainer integrity testing– Pre-sterilization testing.Pre-sterilization testing.– Media fill medium growth promotion testingMedia fill medium growth promotion testing– Sterility TestingSterility Testing– Other microbiological laboratory issuesOther microbiological laboratory issues

Microbiological testing of waterMicrobiological testing of water

WaterWater Water should also be tested for presence of coli forms and/or Water should also be tested for presence of coli forms and/or

pseudomonad's if appropriate (may cause biofilm)pseudomonad's if appropriate (may cause biofilm) Water used for parenterals should be tested for pyrogensWater used for parenterals should be tested for pyrogens

– limit is not more than 0.25 EU/mllimit is not more than 0.25 EU/ml Water should be tested using RWater should be tested using R22A agar (low nutrient for the A agar (low nutrient for the

recovery of water borne organisms) incubated for at least 5 recovery of water borne organisms) incubated for at least 5 days at 30-35°Cdays at 30-35°C

Sampling procedures should follow those used in productionSampling procedures should follow those used in production

Sampling LocationsSampling Locations– Should be based on risk of microbiological contaminationShould be based on risk of microbiological contamination

– Should be clustered around areas where product or Should be clustered around areas where product or components are exposed e.g.components are exposed e.g. at filling heads on filling linesat filling heads on filling lines loading of product into lyophilizersloading of product into lyophilizers stopper bowlsstopper bowls where aseptic connections are madewhere aseptic connections are made where there are high levels of operator activity (but where there are high levels of operator activity (but

without impacting on production)without impacting on production)

Microbiological testing of Air

MethodsMethods Surface monitoringSurface monitoring

– Product contact surfaces, floors, walls, and equipment should be Product contact surfaces, floors, walls, and equipment should be tested on a regular basistested on a regular basis

– Touch plates - used for flat surfacesTouch plates - used for flat surfaces sample area of 25cmsample area of 25cm22

medium protrudes above sidesmedium protrudes above sides medium contains neutralisersmedium contains neutralisers

– Surface Swabs - used for irregular surfacesSurface Swabs - used for irregular surfaces area approx 25cmarea approx 25cm2 2 is swabbedis swabbed qualitative or quantitativequalitative or quantitative

Active Air Monitoring:Active Air Monitoring:

impaction, centrifugal and membrane (or gelatin) impaction, centrifugal and membrane (or gelatin) samplerssamplers

a certain volume of air is sampled (volume and a certain volume of air is sampled (volume and location should be meaningful)location should be meaningful)

instruments should be calibratedinstruments should be calibrated

Passive Air Monitoring:

• Settle plates exposed for 30-60 minutes (longer may result in agar drying out) and replaced for duration of filling• Media should be capable of growing a range of bacteria and moulds. e.g. Soybean Casein Digest Agar (SCDA) • Should consider use of medium specific for moulds if shown to be a problem in the environment • Only give qualitative or semi-quantitative results• Data generated considered in combination with active air sampling results

• Media used for media fills should be able to support the Media used for media fills should be able to support the growth of a wide range of microorganisms (bacteria growth of a wide range of microorganisms (bacteria and moulds)and moulds)

• Soybean Casein Digest Medium is usually used. An Soybean Casein Digest Medium is usually used. An anaerobic medium may also be substituted occasionally anaerobic medium may also be substituted occasionally if environmental monitoring indicates presence.if environmental monitoring indicates presence.

• Media used for microbiological testing should be

tested for its ability to support microbial growth

Media

•After the media fill has been completed, it is important to demonstrate that the media would have been able to support the growth of organisms if they had been present .

•containers with media should be inoculated with 10-100 CFU of organisms such as Bacillus subtilis, Staphylococcus aureus, Candida albicans, Aspergillus niger. Environmental isolates should also be included

Media types:Media types:– Soybean Casein Digest medium (SCD), (also knows as Soybean Casein Digest medium (SCD), (also knows as

Trypticase Soy Broth(TSB)) and Fluid Thioglycollate medium Trypticase Soy Broth(TSB)) and Fluid Thioglycollate medium (FTM) is usually used (to detect aerobic and anaerobic (FTM) is usually used (to detect aerobic and anaerobic organisms)organisms)

– validation studies should demonstrate that the media are capable validation studies should demonstrate that the media are capable of supporting growth of a range of low numbers of organisms of supporting growth of a range of low numbers of organisms in the presence of product. May need to incorporate inactivatorsin the presence of product. May need to incorporate inactivators growth should be evident after 3 days (bacteria), 5 days growth should be evident after 3 days (bacteria), 5 days

(moulds)(moulds)– media may be purchased or made in-house using validated media may be purchased or made in-house using validated

sterilization proceduressterilization procedures

Incubation PeriodIncubation Period– At least 14 days incubationAt least 14 days incubation

– 20-25°C for SCD/TSB, 30-35°C for FTM20-25°C for SCD/TSB, 30-35°C for FTM

– Test containers should be inspected at intervalsTest containers should be inspected at intervals

– temperatures should be monitored and temperature temperatures should be monitored and temperature monitoring devices should be calibratedmonitoring devices should be calibrated

– if product produces suspension, flocculation or deposit in if product produces suspension, flocculation or deposit in media, suitable portions (2-5%) should be transferred to media, suitable portions (2-5%) should be transferred to fresh media, after 14 days, and incubated for a further 7 fresh media, after 14 days, and incubated for a further 7 daysdays

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