Professional Documents
Culture Documents
Manufacturing
Introduction
Togiveanoverviewoftheprinciplesinvolvedinthe
To give an overview of the principles involved in the
manufactureofsterileproducts
Theoverallobjectiveistoproduceproductthathasahigh
assuranceofsterility(andwhichmeetsallotherquality
parameters)
Thispresentation:
Summarisesthegeneralapproach
Givesaframeworkforotherdetailedguidesonspecificaspectsof
sterilisation&sterilemanufacturing
Illustratestheunderlyingprinciples
y gp
p
Providesadviceandgivesrecommendations.
GeneralPrinciplesofSterile
p
Manufacturing
M i t H t St ili ti
MoistHeatSterilization
DryHeatSterilization
AsepticProcessing
Aseptic Processing
EnvironmentalMonitoring
EthyleneOxideSterilization
Ethylene Oxide Sterilization
SterileFiltration
Water systems validation
Watersystemsvalidation
Sterilitytesting
Radiation Sterilization
RadiationSterilization
VisualInspection
Fundementals
S ili is
Sterility
i the
h absence
b
off living
li i organisms
i
This is an absolute definition
The p
probabilityy of achievingg sterilityy depends
p
on the overall p
process
This is a worst
worstcase figure (with a challenge more resistant than product bioburden)
bioburden). Real
confidence levels are generally very much higher
A figure
fi
that
th t has
h sometimes
ti
b
been
quoted
t d for
f aseptically
ti ll filled
fill d product
d t is
i probability
b bilit off non
non
3
sterility of less than 10 . However, this is harder to analyse as contamination does not
follow a clear statistical distribution.
distribution. Potential contamination sources are not randomly
distributed..
distributed
Development Validationand
Control
It is
i important
i
that
h the
h product
d
and
d process are
designed to maximise sterility assurance
Wherever possible, the product should be
developed to withstand sterilization in the final
container
i
Once the product design is defined, a suitable
production process must be developed
This is installed and validated
The process must then be tightly controlled to
assure reliabilityy and consistency.
consistencyy.
Facility Design
FacilityDesign
M
Mustbeincompliancewithcompanypoliciesandprocedures,for
st be in compliance ith compan policies and proced res for
example:
Mustminimisetheriskofcontaminationatallcriticalstages
R
RequiredGradesofCleanRooms:needtobeappropriateforthe
i dG d
f Cl
R
d b
i
f h
process e.g.forTerminalSterilizationorAsepticFill
process
PersonnelAccessandMaterialFlow
Restrictedaccess,correctgowning
R
i d
i
Materialsflow,airlocks,decontamination,segregation
HVAC
HVACSystem
Segregation/DedicatedHVACofcorrectstandard
RequirescontrolofFiltration/P/AirFlow/Temp./Pressure/Humidity
Airflowpatternsdemonstrated
f
p
NosinksanddrainsinZoneA/Bareas,airbreakstodrainsinothers
Surfacesandeaseofcleaning:smoothunbrokenimpervioussurfaces
Cleaninganddisinfectionofthe
Facility
Cleaning
Cleaninganddisinfectionisimportantinenvironmentalcontrol
and disinfection is important in environmental control
Efficacyneedstobevalidated
Validatedprocedures,conductedconsistently
InclassA&Bareas,thecleaninganddisinfectantmaterialsmustbe
I l
A&B
h l
i
d di i f
i l
b
sterilized
Andneedtominimisecontaminationriskinotherareas
Operatingproceduresmustinclude,atminimum:
i
d
i l d
i i
Preparationofcleaningmaterials(andsterilizationifapplicable)
Exactprocedureofcleaning&disinfection.
Responsibility&scheduling.
Typeandconcentrationofdetergentsanddisinfectants.
Typeofcleaningtools.
Trainingisrequiredforcleaninganddisinfectionof
Trainingisrequiredforcleaninganddisinfectionofcleanrooms
cleanrooms
Routinedecontaminationusingformaldehydegasshouldbeavoided.
Water
All
Allwatersystemsrequiregooddesignandvalidation
t
t
i
dd i
d lid ti
yp
y,
pharmacopoeial
p
p
ggrades,validationincludes
,
Typically,forpharmacopoeial
Typically,for
Twostudiesoveratotalof4weekstoassessagainsttheacceptancecriteria,
Additional11monthstoverifythatthesystemremainsundercontrol
Mustdemonstrateconsistentproductionofwaterofthe
Must demonstrate consistent production of water of the
requiredquality
Physico
Physicochemical,
Microbiological,
Biological(
Biological(endotoxin
endotoxin,whereapplicable)
,whereapplicable)
Watersystemsmustberegularlymonitoredfollowinga
Water systems must be regularly monitored following a
definedwrittenmonitoringplanbasedonresultsofthe
validationstudies.
Categories of Water
CategoriesofWater
Water
W t for
f Injections
I j ti
(WFI)
For injectables formulation
Final rinse water ffor p
productcontact items (f
product
(for injectables
injectables)
j
)
Freshly prepared or from a validated hot (e
(e..g., >75
75C) storage
/distribution system or otherwise protected from microbial
contamination
o a
a o
VacuumSystems
y
Sometimesusedforcleaninganddustcontrol
Maybemobileunits,fittedwithexhaustHEPAfilters
Or
Ormayhavecentraldustcollection
may have central dust collection
Onthese,usededicatedvacuumpumpsprotectedagainstback
Onthese,usededicatedvacuumpumpsprotectedagainstbackflow
Designtopreventunprotectedrouteintotheasepticsuite.
Equipment (1)
Equipment(1)
EquipmentQualification
E i
t Q lifi ti
Toincludethecriticalaspectsforsterileproductprocessing
Qualificationofcriticalaspectsofmoistheatsterilization,aseptic
f
f
p
f
,
p
processing,dryheatsterilizationetc.
CleaningandSanitizationofEquipment
Equipmentdesignedforeasycleaningandsanitization
Equipment designed for easy cleaning and sanitization
ForTerminalSterilizationapplications,lowmicrobialchallenge.
Wherepossible,criticalsurfacesshouldbesterilized
Forasepticwork,thecritical(productcontact)surfacesmustbe
For aseptic work the critical (product contact) surfaces must be
sterilizedbeforeuse.Inexceptionalcaseswherethisisnotpossible
(e.g.,somestopperbowls),theyshouldbesanitizedbyavalidated
method
Cleaningvalidationmustshoweffectivenessandabsenceofresidues.
Equipment (2)
Equipment(2)
Equipment
i
S ili i and
Sterilization
d handling
h dli
Sterilization must follow a validated procedure
Aseptic processes designed to minimise aseptic
assembly and intervention
Unavoidable
U
id bl aseptic
i assembly
bl needs
d clear
l
& precise
i
procedures
Aseptic assembly must be simulated (worst
(worstcase) in
media fill simulation trials
Personnel
Training
T i i
personnell appropriately
i t l trained
t i d for
f
sterile
t il
processing, including assessment and documentation:
documentation:
Basic GMP
Fundamentals
d
l off microbiology
b l
Personal hygiene, health and cleanliness
Behaviour and aseptic working techniques
G
Gowning
i and
d entry
t procedures
d
Cleaning and disinfection
Sterilization procedures, validation and routine operation
Emergency procedures to protect product quality (e
(e..g. loss of HVAC System,
System
loss of power, equipment interventions etc
etc..)
Gowning
Personnelmustcorrectlywearappropriatecleanroomgarments
Detailed,easilyunderstood,gowningprocedure(preferablyillustrated)
AsepticTechniques
Personnelintheasepticmanufacturingarea,mustunderstandtheprinciples
of aseptic procedures
ofasepticprocedures
Theymustonlybeconsideredqualifiedafterappropriatetraining,working
undersupervisionanddemonstrationofcompetence
Thesupervisorshouldobservetechnique&correctasnecessary
Allpersonneldirectlyinvolvedinasepticprocessingmustparticipateina
mediafillatleastonceperyear
Gl
Glovedisinfection
di i f ti
Steriledisinfectantsmustbeavailable(e.g.,alcoholbased)
Glovedisinfectionmustbereasonablyfrequent,definedinSOP.
OperationalQualification(OQ)atrestconditionstoverifyoperation
PerformanceQualification(PQ)inworstcaseoperationalconditions
ActionlevelsshouldmeetUSPorEuroGMPasapplicable
Alertlevelstightenoughtodetectdeterioration,butnotsotightthat
theybecomemeaninglessduetofrequenttransgression
PQmustcoverasufficientperiodtoestablishconsistency
RoutineMonitoring
Ensuresarearemainssatisfactory.Resultsshouldbewithinalertlevel
f
y
Resultsabovealertlevelsneedreviewandperhapscorrectiveactions
Aboveactionlevels,musttriggerappropriateactions(describedin
g
guide),
),
Resultsmustbeassessedfortrendssothatprogressiveorsudden
changesintheresultsmaybeobserved.Thisshouldbereviewed
regularly.
RecommendedMethodsforRoutineMonitoring
Thedatamustbeanalysed
Wherenecessaryfurtherinvestigationsinitiated
Possible contamination sources to be assessed and eliminated
Possiblecontaminationsourcestobeassessedand,eliminated
Outcomeanddetailmustbereported
Physicalmeasurementsoftheairsupply
Physical
measurements of the air supply
Physicalandmicrobiologicalmonitoringoftheenvironment
Particles(viableandnonviable)intheair
Microorganisms settling out of the air
Microorganismssettlingoutoftheair
Microorganismscontaminatingsurfaces
Presenceofmicroorganismsonthehandsandgarments
Monitoring Plan
MonitoringPlan
Definedmonitoringplans:tests,locations,alert/actionlevels&frequencies
Maycontaindetailsofwater,compressedgascleansteamtesting
Areviewofenvironmentaldataisarequirementforbatchrelease.
A review of environmental data is a requirement for batch release.
Bioburden andComponents
and Components
MaterialsUsedintheProcess
Whereappropriate,determinebioburden (e.g.,ionexchangematerials)
PrimaryPackagingComponents
Containerandtheclosureandcleaning/sterilizationtobeclearlyspecified
Stepssuchassiliconization
p
mayneedmonitoring
y
g
Ifcleaning/sterilizationisbysupplier,sameexigenciesapply
Containerclosureintegrity
Container
Theintegritymustbevalidated
The integrity must be validated
Simulate,whereappropriate:stressfromprocessing
Methodappropriatetocontainer/closuresystem
Weighing,Compunding and
Sterilization
Weighing
Weighingandcompoundingmustbeinsuitablyclassifiedrooms
and compounding must be in suitably classified rooms
Vesselsmustbecleaned,andsterilizedorsanitisedasappropriateandstoreddry
inawaytopreventmicrobialcontamination
Storageofpresterilizationintermediatestobecontrolled&timelimited
Storageofpre
Followingaspectstobeconsidered:
Prefiltrationbioburden
Pre filtration bioburden (filtersterilizedmaterial)
(filter sterilized material)
Presterilizationbioburden
Appropriateinprocesscontrols
Sterilizationofproductandproductcontactmaterials
SelectionofasuitablesterilizationprotocolmustbebasedonSAL
Methodmustalsoconsiderthestabilityoftheproduct
Method must also consider the stability of the product
Validationalwaysrequired
Changecontrolisvital;evenapparentlyminorchangemustbeassessed
Terminal Sterilization
TerminalSterilization
Steam Sterilization
SteamSterilization
Byfarthemostcommonmethodforaqueousbasedpharmaceuticals
PreferredcycleisthePharm Eur referencecycleis15minutesat121C
The sterilization cycle chosen must be compatible with product stability
Thesterilizationcyclechosenmustbecompatiblewithproductstability
Sterilizationparametersclearlydefined
Inconjunctionwithothercontrols,therequiredSALmustbedemonstrated
Validationtoconfirmsterilizationconditionsconsistentlythroughouttheload
SterilizationbyIonizingRadiation
Commonformedicaldevices,butnotforpharmaceuticals.
Pharm.Eur.referencecondition,25KiloGray (kGy),hasbeenwidelyaccepted.Other
conditions may be used if validated and accepted by the regulator
conditionsmaybeusedifvalidatedandacceptedbytheregulator
Importanttoconsidersusceptibilityoftheproducttoradiationdamage
DryHeatSterilization
Lower
Lowerantimicrobialefficacythanmoistheat,thushighertemperaturesand/orlonger
antimicrobial efficacy than moist heat thus higher temperatures and/or longer
exposures.Pharm Eur referencecycleis2hours@160C
Rarelyusedforterminalsterilizationofpharmaceuticals;inrarecasesheatresistantnon
aqueousproductsmaybeterminallysterilized.
SterilizationofItemsforAsepticFill
(1)
Steam Sterilization
SteamSterilization
Widelyused,butcarefulvalidationneeded particularlycomplexitems
Broadlysimilartoterminalsteamsterilization,buttwoaspectsarecritical
Qualityofsaturatedsteam
Quality of saturated steam
Removalofairandsubsequentsteampenetration
SterilizationbyIonizingRadiation
Maybeusedfortemperaturesensitiveprimarypackagingorcomponents
Usedfordisposablesforsterileareasandsterilitytestingareas
Validationincludesdosimetry, correct,even,irradiationoftheitems
DryHeatSterilization/
DryHeatSterilization/Depyrogenation
Depyrogenation
Sterilization/depyrogenation ofheatresistantprimarypackagingmaterials
Pharm Eur notesthattemperaturesinexcessof220oChavebeenfrequently
used,theUSPsuggests250 15oC
Validationmustincludeendotoxin
V lid ti
ti l d
d t i challengestudies
h ll
t di
Dryheatmaybeusedtosterilizenonaqueouspreparations(e.g.Ointment
bases)atlowertemperature/timerelationships,withoutdepyrogenation.
SterilizationofItemsforAsepticFill
(2)
EthyleneOxideSterilization
Eth lene O ide Sterili ation
Quitewidelyusedtosterilizeheatlabilecomponents
EuropeanPharmacopoeiaandtheEuropeanGMPguideindicatethat
thi
thismethodshouldonlybeusedwherethereisnosuitable
th d h ld l b
d h
th
i
it bl
alternative
Hazardous toxic,potentiallycarcinogenic,flammable,potentially
explosive
Generallyconductedbyspecializedcontractors
Therearestrictregulatorylimitsonmaximumpermissibleproduct
residues
Bulkpacksforsterilizationmustbegaspermeable,butsealed
againstmicrobialingress
Sterilizationmustconsiderpackaging,loadpattern,gaspenetration
Sterilization must consider packaging load pattern gas penetration
(ethyleneoxide&watervapour),bulkpackintegrity
ValidationandroutinemonitoringmustincludeBiologicalindicators.
Principle:
Contaminatingorganismsarenotkilled,butareretainedonthefilters.Anyfaultsinthe
filterstructure,maycompromisethis
Validationincludes:
Retentionofbacterialchallenge:B.diminuta at107percm2
Thisiscorrelatedwithanintegritytestvalue
Validationshouldaddress:
Filtersuitability toxicity,extractables,sheddingofparticles
Adsorptionofproduct
Compatibilitywithproductsolvents
Therequiredfiltersizeandsuitabilityofthefiltrationequipment
h
i d fil
i
d i bili
f h fil
i
i
RetentionofB.diminuta intheactualproductunderprocessconditions
Parametersforthephysicalintegritytest
RoutineFiltration
Routine Filtration
Conductedinlinewiththevalidatedparameters
Checkintegritytesting,processtime,differentialpressure,flowrates,sterilizationandreuse
offilters.
PerformanceQualificationofAseptic
Manufacturing
Based on simulating the risk of contamination in all
aseptic operations
For a new process, a minimum of three consecutive
satisfactory media filling trials
For aqueous liquid products, simulation trials use a
liquid microbiological medium
For solid dosage forms, a powder placebo is used,
followed by aseptic reconstitution into a liquid
microbiological
b l
l medium
d
The following slide gives a general overview
overview....
....
AsepticProcessSimulation
(MediaFillTrial)
MediaFillTrials(MFTs)
Media Fill Trials (MFTs)
Allprocessstagessimulatedascloselyaspossible
Particularlyinterventionsandmanualmanipulations
Mustfollowroutineproceduresandincludeallinterventions
Regularinterventionssimulatedwiththesamefrequencyasactualprocess
Ineachcase,theworstcaseeventualitymustbecovered
Processmustbesuccessfullyvalidatedbeforeproductfillingispermitted
Revalidationbymediafillmustbeconductedeveryhalfyear(eachline)
ManufacturingEnvironment
g
Microbiologicalmonitoringmustbeperformedduringthetrial
FillingConditionsandEquipment
Allaccordingtoroutineoperatingconditionsandatnormaltimesofday
All according to routine operating conditions and at normal times of day
Containersmustbepassedthroughallstages.
Thank You
Any Questions