The document discusses water systems used in the pharmaceutical industry. It provides details on the types of water needed (e.g. purified water, water for injections), how water is treated and purified using various methods (e.g. multimedia filtration, softening, reverse osmosis, deionization), requirements for water quality depending on its intended use (e.g. sterile products, API manufacture), and validation of water systems to ensure water meets quality standards. Tables outline appropriate water grades for different uses and cleaning requirements.

1. WATER VALIDATIONWATER VALIDATION
Dr. Vineet Bhushan
Ind-Swift Limited
Global Business UnitGlobal Business Unit
Derabassi, Punjab.

2. WATERWATER
AGENDAAGENDAAGENDAAGENDA
Usage of Water in Pharmaceutical IndustryUsage of Water in Pharmaceutical IndustryUsage of Water in Pharmaceutical Industry.Usage of Water in Pharmaceutical Industry.
Understanding Water System.Understanding Water System.
Water System Validation.Water System Validation.
Compliance Assessment of Water System.Compliance Assessment of Water System.

3. WATERWATER
WaterWater isis oneone ofof thethe majormajor commoditiescommodities usedused byby thethe
pharmaceuticalpharmaceutical industryindustry.. ItIt maymay bebe usedused asas
AnAn excipientexcipientAnAn excipientexcipient
ForFor reconstitutionreconstitution ofof productsproducts
DuringDuring synthesissynthesis
DuringDuring productionproduction ofof thethe finishedfinished productproductgg pp pp
AsAs aa cleaningcleaning agentagent forfor rinsingrinsing vessels,vessels, equipment,equipment,
primaryprimary packagingpackaging materialsmaterials etcetc..

4. WATERWATER
ffff ffDifferentDifferent GradeGrade ofof WaterWater
Potable WaterPotable WaterPotable WaterPotable Water
Purified WaterPurified Water
Highly Purified WaterHighly Purified Water
Water for InjectionsWater for Injections

5. WATERWATERWATERWATER
OPOTABLE WATER
Potable water may be used in chemical synthesis and in the
early stages of cleaning pharmaceutical manufacturing
equipment unless there are specific technical or qualityequipment unless there are specific technical or quality
requirements for higher grades of water.

6. WATERWATERWATERWATER
PURIFIED WATER
Purified Water is water for the preparation of medicinal
products other than those that require the use of water which
is sterile and/or apyrogenicis sterile and/or apyrogenic.
Purified Water which satisfies the test for endotoxins may be
d i th f t f di l i l tiused in the manufacture of dialysis solutions

7. WATERWATERWATERWATER
GHIGHLY PURIFIED WATER
Highly Purified Water is intended for use in the preparation
of products where water of high biological quality is needed,
except where Water for Injections is requiredexcept where Water for Injections is required

8. WATERWATERWATERWATER
WATER FOR INJECTIONS
Water for Injections (WFI) is water for the preparation of
medicines for parenteral administration when water is used
as a vehicle (water for injections in bulk) and for dissolving oras a vehicle (water for injections in bulk) and for dissolving or
diluting substances or preparations for parenteral
administration before use (sterilised water for injections).

9. WATERWATERWATERWATER
QUALITY OF WATERQ
FOR PHARMACEUTICAL USE

10. WATERWATERWATERWATER
Table 1: Sterile Medicinal Products
Sterile medicinal products Minimum acceptable quality of
water
Parenteral WFIParenteral WFI
Ophthalmic Purified
Haemofiltration Solutions WFI
Haemodiafiltration Solutions
Peritoneal Dialysis Solutions WFI
Irrigation Solutions WFIIrrigation Solutions WFI
Nasal/Ear Preparations
Cutaneous Preparations
Purified
Purified

11. WATERWATERWATERWATER
Table 2:Table 2: NonNon--sterile Medicinal Productssterile Medicinal Products
Non-sterile medicinal products Minimum acceptable quality ofp p q y
water
Oral Preparations Purified
Nebuliser Solutions PurifiedNebuliser Solutions Purified
Cutaneous Preparations Purified
Nasal/Ear Preparations Purified
Rectal/Vaginal Preparations Purified

12. WATERWATER
Table 3 Water used during the manufacture of Active PharmaceuticalTable 3 Water used during the manufacture of Active Pharmaceutical IngredientsIngredients
Type of manufacture Product requirements Minimum acceptable quality of
water
Table 3 Water used during the manufacture of Active PharmaceuticalTable 3 Water used during the manufacture of Active Pharmaceutical IngredientsIngredients
(APIs)(APIs)
Synthesis of all intermediates of APIs
prior to final isolation and purification
steps
No requirement for sterility or apyrogenicity in API
or the pharmaceutical product in which it will be
used.
Potable Water
Fermentation media No requirement for sterility or apyrogenicity in API
h h i l d i hi h i ill b
Potable Water
or the pharmaceutical product in which it will be
used
Extraction of herbals No requirement for sterility or apyrogenicity in API
or the pharmaceutical product in which it will be
used
Potable Water
Final isolation and
purification
No requirement for sterility or apyrogenicity in API
or the pharmaceutical product in which it will be
used
Potable Water
Final isolation and
purification
API is not sterile, but is intended for use in a sterile,
non parenteral product
Purified Water
purification non-parenteral product
Final isolation and
Purification
API is sterile and not intended for parenteral use Purified Water
Final isolation and
Purification
API is not sterile, but is intended for use in a sterile,
parenteral product
Purified Water with an endotoxin
limit of 0.25EU/ml and controlp p
of specified organisms.
Final isolation and
purification
API is sterile and apyrogenic Water For Injections

13. WATERWATERWATERWATER
Table 4:Table 4: Water used during manufacture of medicinalWater used during manufacture of medicinal
products which is not present in the finalproducts which is not present in the finalproducts which is not present in the finalproducts which is not present in the final
formulationformulation
Manufacture Minimum acceptable quality ofManufacture Minimum acceptable quality of
water
Granulation Purified
T bl t ti P ifi dTablet coating Purified
Used in formulation prior to non-
sterile
l hili ti
Purified
lyophilisation
Used in formulation prior to sterile
lyophilisation
WFI

14. WATERWATERWATERWATER
Table 5:Table 5: Water used for cleaning/rinsing.Water used for cleaning/rinsing.
Cleaning/Rinsing of Equipment, Containers,
Closures
Product type Minimum Acceptable
quality of water
Initial rinse Intermediates and API Potable Water
Final rinse API Use same quality of water as
used in the API manufacture
Initial rinse including CIP of equipment,
containers and closures, if applicable.
Pharmaceutical products –
non sterile
Potable Water
Fi l i i l di CIP f i t Ph ti l d t P ifi d W t lit f tFinal rinse including CIP of equipment,
containers and closures, if applicable.
Pharmaceutical products –
non sterile
Purified Water or use same quality of water as
used in manufacture of medicinal product, if
higher quality than Purified Water
Initial rinse including CIP of equipment,
containers and closures if applicable
Sterile products Purified Water
containers and closures, if applicable.
Final rinse including CIP of equipment,
containers and closures, if applicable.
Sterile non-parenteral
products
Purified Water or use same quality of water as
used in manufacture of medicinal
product, if higher quality than Purified Water
Final rinse incl ding CIP of eq ipment Sterile parenteral prod cts WFIFinal rinse including CIP of equipment,
containers and closures, if applicable.
Sterile parenteral products WFI

15. WATERWATERWATERWATER
Why Water system Validation ?Why Water system Validation ?Why Water system Validation ?Why Water system Validation ?

16. WATERWATERWATERWATER
Contaminants of waterContaminants of water
There is nThere is no pure water in natureo pure water in nature, as it can, as it can
contain up tocontain up to 90 possible unacceptable90 possible unacceptable
contaminantscontaminantscontaminantscontaminants
Contaminant groups:Contaminant groups:
IInorganicnorganic compoundscompounds
OrOrgagannic compoundsic compounds
SolidsSolids
GasesGases
MicroorganismsMicroorganismsMicroorganismsMicroorganisms

17. WATERWATERWATERWATER
Contaminants of waterContaminants of water
Problem mProblem mineralsinerals
Calcium, magnesium, cCalcium, magnesium, copper, aluminium, heavyopper, aluminium, heavy
metals, arsenic, lead, cadmium, nitratesmetals, arsenic, lead, cadmium, nitrates, , , ,, , , ,
Iron, manganese, silicates, carbon dioxideIron, manganese, silicates, carbon dioxide
Hydrogen sulfideHydrogen sulfide
PhosphatesPhosphates

18. WATERWATER
Contaminants of waterContaminants of water
MicroorganismsMicroorganisms –– Biofilm formationBiofilm formation
ProtozoaProtozoaProtozoaProtozoa
–– CryptosporidiumCryptosporidium
–– GiardiaGiardia
BacteriaBacteria
–– PseudomonasPseudomonas
–– Gram negative, nonGram negative, non--fermenting bacteriafermenting bacteria
–– Escherichia coli and coliformsEscherichia coli and coliforms

19. WATERWATER
Biofilm formationBiofilm formation
FreeFree--swimming aquatic bacteria useswimming aquatic bacteria use
polymucosaccharides to colonipolymucosaccharides to colonizze surfacese surfacesp yp y
Complex communities evolve which shedComplex communities evolve which shed
microcolonies and bacteriamicrocolonies and bacteria

20. WATERWATERWATERWATER
S d d S h j bS d d S h j bStandard Water System has two major sub systemsStandard Water System has two major sub systems
1)1) Pre Treatment SectionPre Treatment Section
2)2) Storage & Distribution SectionStorage & Distribution Section2)2) Storage & Distribution SectionStorage & Distribution Section

21. WATERWATERWATERWATER
PRODUCTIONPRODUCTIONPRODUCTIONPRODUCTION
PurifiedPurified waterwater systemsystem productionproduction equipmentequipment commonlycommonly
includesincludes
M lti diM lti di filtfiltMultimediaMultimedia filtersfilters
SoftenersSofteners
ActivatedActivated carboncarbon filtersfilters
ReverseReverse osmosisosmosis unitsunitsReverseReverse osmosisosmosis unitsunits
DemineralizersDemineralizers
UltrafiltrationUltrafiltration equipmentequipment..

22. WATERWATERWATERWATER

23. WATERWATERWATERWATER
Multimedia FiltrationMultimedia Filtration
SuspendedSuspended solidssolids areare removedremoved fromfrom thethe makeupmakeup waterwater
utilizingutilizing multimediamultimedia filtersfilters.. TheseThese vesselsvessels areare pressurizedpressurized andand
containcontain layerslayers ofof gradedgraded grant,grant, sand,sand, andand anthraciteanthracite..

24. WATERWATERWATERWATER
S ft iS ft iSofteningSoftening
HardnessHardness elementselements areare removedremoved byby passingpassing thethe waterwater throughthrough
vesselsvessels containingcontaining cationcation resinresin..

25. WATERWATERWATERWATER
i d C bi d C bActivated CarbonActivated Carbon
ActivatedActivated carboncarbon filtersfilters removeremove chloridechloride foundfound onon thethe makeupmakeup
thusthus preventingpreventing reversereverse osmosisosmosis membranemembrane degradationdegradation..

26. WATERWATERWATERWATER
Reverse OsmosisReverse OsmosisReverse OsmosisReverse Osmosis
ThisThis methodmethod generallygenerally providesprovides forfor 9090--9595%% rejectionrejection ratesrates forfor bothboth
inorganicinorganic andand organicorganic impuritiesimpurities DueDue toto thethe possibilitypossibility ofof bacterialbacterialinorganicinorganic andand organicorganic impuritiesimpurities.. DueDue toto thethe possibilitypossibility ofof bacterialbacterial
growgrow--through,through, thethe reversereverse osmosisosmosis systemsystem mustmust bebe aa “double“double pass”pass”
designdesign..
ThinThin--filmfilm compositecomposite (TFC)(TFC) membranesmembranes composedcomposed ofof aa polyamidepolyamide filmfilm
withwith aa polysulfonepolysulfone supportingsupporting structurestructure areare usedused.. TheseThese membranesmembranes
havehave::
LowerLower openingopening pressurespressures
ExcellentExcellent rejectionrejection ofof silicasilica andand monovalentmonovalent ionsions
EffectivenessEffectiveness overover aa broadbroad pHpH rangerange
ResistanceResistance toto bacterialbacterial attackattack
TypicalTypical TFCTFC membranesmembranes removeremove greatergreater thanthan 9797%% ofof thethe feedwaterfeedwater
ionicionic impuritiesimpurities..

27. WATERWATERWATERWATER
Reverse osmosis (RO) theory
High pressure Low pressure
Reverse osmosis (RO) theory
Feed
water
Semi-perm
membra
raw water
under
pressure
meable
ane
Purified water
R
w
P
Reject
water
Permeate
water
drain or recycle

28. WATERWATERWATERWATER
Water from softener or de-ioniser
Typical 2-stage RO schematic
Branch
Branch
ntrate
Second stage reject water goes back to first stage buffer tank
1st stage buffer tank
First stage RO cartridge
First stage filtrate feeds second stage RO
with excess back to 1st stage buffer tank.
gerejectconcen
2nd stage buffer tankSecond stage RO cartridge
1ststa
Air break
to sewer
Hi h
Cartridge
filter 1 µm
Second stage RO water
meets Pharmacopoeia
standards Outlets or storage
Water returns to 1st stage buffer tank
Hygienic pump
High pressure
pump
Outlets or storage

29. WATERWATERWATERWATER
Mixed Bed PolishingMixed Bed PolishingMixed Bed PolishingMixed Bed Polishing
MixedMixed bedbed polisherspolishers receivereceive aa highhigh puritypurity waterwater influentinfluent
furtherfurther decontaminatedecontaminate thethe streamstream.. TheThe drivingdriving forceforce inin ionionfurtherfurther decontaminatedecontaminate thethe streamstream.. TheThe drivingdriving forceforce inin ionion
exchangeexchange isis thethe concentratedconcentrated differentialdifferential betweenbetween thethe ionion onon
thethe beadbead andand inin solutionsolution..
CationCation resinsresins removeremove contaminantscontaminants suchsuch asas calcium,calcium,CationCation resinsresins removeremove contaminantscontaminants suchsuch asas calcium,calcium,
magnesiummagnesium andand sodiumsodium..
CationCation ResinResin RR--HH ++ NaNa++ ------ RR--NaNa ++ HH++
AnionAnion resinsresins removeremove contaminantscontaminants suchsuch asas bicarbonatebicarbonateAnionAnion resinsresins removeremove contaminantscontaminants suchsuch asas bicarbonate,bicarbonate,
sulfatesulfate andand chloridechloride..
AnionAnion ResinResin RR--OHOH ++ CC11-- ------ RR--CC11 ++ OHOH--
DemineralizersDemineralizers cancan onlyonly removeremove aa finitefinite amountamount ofof impuritiesimpuritiesDemineralizersDemineralizers cancan onlyonly removeremove aa finitefinite amountamount ofof impuritiesimpurities
beforebefore requiringrequiring regenerationregeneration withwith eithereither causticcaustic (anion(anion resin)resin)
oror acidacid (cation(cation resin)resin)..

30. WATERWATERWATERWATER
C i i i iC i i i iContinuous DeionizationContinuous Deionization
ContinuousContinuous deionizationdeionization (CDI)(CDI) combinescombines thethe useuse ofof resins,resins,
selectiveselective membranesmembranes andand directdirect currentcurrent toto removeremove
contaminantscontaminantscontaminantscontaminants

31. WATERWATERWATERWATER
l fil il fil iUltrafiltrationUltrafiltration
UltrafiltrationUltrafiltration membranesmembranes areare thethe finalfinal treatmenttreatment inin thethe
productionproduction processprocess.. TheseThese areare usedused toto assureassure
RemovalRemoval ofof microbialmicrobial organismsorganisms
ColloidsColloids
AnyAny otherother remainingremaining contaminantscontaminants..

32. WATERWATERWATERWATER
Di till tiDi till tiDistillationDistillation
IfIf thethe waterwater isis designateddesignated forfor waterwater forfor injectioninjection (WFI)(WFI) usage,usage,
thenthen effluenteffluent fromfrom thethe purifiedpurified waterwater schemescheme isis furtherfurther refinedrefined
usingusing distillationdistillation toto removeremove ions,ions, TOC,TOC, bacteriabacteria andand
d id iendotoxinsendotoxins..

33. WATERWATERWATERWATER
Storage & DistributionStorage & Distribution
StorageStorage andand distributiondistribution componentscomponents includeinclude storagestorage tanks,tanks,
pumps,pumps, piping,piping, valves,valves, heatheat exchangesexchanges andand instrumentationinstrumentation
necessarynecessary toto guaranteeguarantee thethe deliverydelivery ofof aa highhigh qualityquality productproductnecessarynecessary toto guaranteeguarantee thethe deliverydelivery ofof aa highhigh qualityquality productproduct
toto thethe pointpoint--ofof--useuse..

35. WATERWATERWATERWATER
Storage TanksStorage TanksStorage TanksStorage Tanks
WaterWater storagestorage tankstanks areare designeddesigned forfor aa minimumminimum pressurepressure ofofgg gg pp
3030 psigpsig andand fullfull vacuumvacuum.. ToTo preventprevent microbialmicrobial growthgrowth andand
contamination,contamination, excessiveexcessive storagestorage capacitycapacity isis limitedlimited andand thethe
waterwater isis continuouslycontinuously recirculatedrecirculated..
SteamSteam jacketingjacketing thethe storagestorage tanktank isis aa commoncommon designdesign practicepractice
andand providesprovides aa heatheat sourcesource forfor thethe contents,contents, thusthus savingsaving onon
heatheat exchangerexchanger costscosts..
SteamSteam jacketedjacketed ventvent filtersfilters withwith aa 00..22 umum hydrophobichydrophobic
cartridge,cartridge, sanitarysanitary clampclamp connection,connection, andand condensatecondensate lineline onon
thethe dirtydirty sideside ofof thethe filterfilter minimizeminimize thethe ingressingress ofof
i ii i hilhil hh kk “b h ”“b h ”contaminationcontamination whilewhile thethe tanktank “breaths”“breaths”..

36. WATERWATERWATERWATER
Heat Exchangers & PumpsHeat Exchangers & PumpsHeat Exchangers & PumpsHeat Exchangers & Pumps
HeatHeat exchangersexchangers provideprovide anan interfaceinterface wherewhere highhigh puritypurity waterwater
cancan easilyeasily becomebecome contaminatedcontaminated..
CentrifugalCentrifugal pumpspumps withwith sanitarysanitary connections,connections, doubledouble
mechanicalmechanical seals,seals, highhigh puritypurity waterwater flushflush andand tangentialtangential
casingcasing draindrain forfor completecomplete draining,draining, shouldshould bebe specifiedspecified..

37. WATERWATERWATERWATER
i i & li i & lPiping & ValvesPiping & Valves
TheThe distributiondistribution looploop shouldshould bebe asas shortsshorts asas possiblepossible toto avoidavoid
hi hhi h dd i li l i ii i ThTh iihighhigh pressurespressures andand potentialpotential contaminationcontamination.. TheThe equipmentequipment
shouldshould bebe designeddesigned forfor sanitization,sanitization, cleanability,cleanability, preventativepreventative
maintenancemaintenance andand futurefuture needsneeds..
Ph ti lPh ti l i ii i ff tt ithith h th t iti tiiti tiPharmaceuticalPharmaceutical pipingpiping forfor aa systemsystem withwith heatheat sanitizationsanitization
wouldwould utilizeutilize
316316LL t i lt i l t lt l316316LL stainlessstainless steelsteel
ButtButt weldedwelded (or(or sanitarysanitary clamps)clamps)
NoNo threadedthreaded jointsjoints..
TheThe pipingpiping isis slopedsloped atat 11//88”” perper footfoot toto provideprovide drainagedrainage
duringduring idleidle periodsperiods..

38. WATERWATERWATERWATER
InstrumentationInstrumentationInstrumentationInstrumentation
InstrumentationInstrumentation provides a means of continuouslyprovides a means of continuously
monitoring he distribution loop for flow quantity andmonitoring he distribution loop for flow quantity and
quality.quality.

39. WATERWATERWATERWATER
Validation of Water SystemValidation of Water System

40. WATERWATERWATERWATER
lid i i ilid i i iValidation PrerequisitesValidation Prerequisites
TheThe validationvalidation acceptanceacceptance criteriacriteria shouldshould bebe specifiedspecified inin thethe
User,User, Functional,Functional, andand DesignDesign SpecificationsSpecifications.. IfIf thethe
specificationsspecifications areare poor,poor, partsparts missing,missing, oror nonexistent,nonexistent, thenthenspecificationsspecifications areare poor,poor, partsparts missing,missing, oror nonexistent,nonexistent, thenthen
validationvalidation cannotcannot proceedproceed..

41. WATERWATERWATERWATER
lid i i ilid i i iValidation PrerequisitesValidation Prerequisites
TheThe UserUser SpecificationSpecification shouldshould havehave beenbeen thethe firstfirst specificationspecification
writtenwritten.. Theoretically,Theoretically, itit comprisescomprises crucialcrucial informationinformation aboutabout
thethe qualityquality andand quantityquantity ofof waterwater thatthat thethe useruser demandsdemands..thethe qualityquality andand quantityquantity ofof waterwater thatthat thethe useruser demandsdemands..

42. WATERWATERWATERWATER
lid i i ilid i i iValidation PrerequisitesValidation Prerequisites
FunctionalFunctional SpecificationSpecification.. ItIt containscontains allall thethe importantimportant datadata
relatedrelated toto pumps,pumps, piping,piping, valves,valves, tanks,tanks, instrumentation,instrumentation, etcetc..
thisthis documentdocument isis thethe basisbasis forfor thethe OperationalOperational QualificationQualificationthisthis documentdocument isis thethe basisbasis forfor thethe OperationalOperational QualificationQualification
(OQ)(OQ) protocolprotocol..

43. WATERWATERWATERWATER
lid i i ilid i i iValidation PrerequisitesValidation Prerequisites
TheThe DesignDesign SpecificationSpecification hashas allall thethe equipmentequipment lists,lists, drawings,drawings,
andand vendervender informationinformation thatthat willwill bebe neededneeded toto generategenerate anan
InstallationInstallation QualificationQualification (IQ),(IQ), P&IDs,P&IDs, isometricisometric drawingsdrawings andandInstallationInstallation QualificationQualification (IQ),(IQ), P&IDs,P&IDs, isometricisometric drawingsdrawings andand
otherother documentsdocuments areare requisiterequisite forfor verificationverification ofof asas--builtbuilt toto
designdesign..

44. WATERWATERWATERWATER
lid i i ilid i i iValidation PrerequisitesValidation Prerequisites
DuringDuring thethe HPWHPW SystemSystem constructionconstruction phase,phase, equipmentequipment willwill bebe
challengedchallenged andand operationoperation verifiedverified priorprior toto commissioningcommissioning andand
validationvalidation utilizingutilizing writtenwritten factoryfactory tests,tests, factoryfactory acceptanceacceptancevalidationvalidation utilizingutilizing writtenwritten factoryfactory tests,tests, factoryfactory acceptanceacceptance
tests,tests, andand sitesite acceptanceacceptance teststests protocolsprotocols..

45. WATERWATERWATERWATER
I t ll ti Q lifi tiI t ll ti Q lifi tiInstallation QualificationInstallation Qualification
ThTh I ll iI ll i Q lifi iQ lifi i ff i li l hhTheThe InstallationInstallation QualificationQualification ofof aa waterwater systemsystem involvesinvolves thethe
verificationverification ofof thethe designdesign installationinstallation.. TheThe followingfollowing itemsitems
shouldshould bebe verifiedverified andand documenteddocumented::
Welding,Welding, Hydrostatic,Hydrostatic, andand FilterFilter IntegrityIntegrity TestingTesting
PassivationPassivation
PipingPiping SlopeSlope
AsAs--BuiltBuilt P&IDP&ID
Utilities,Utilities, Equipment,Equipment, andand InstrumentationInstrumentation InstallationInstallationUtilities,Utilities, Equipment,Equipment, andand InstrumentationInstrumentation InstallationInstallation
ControlControl SystemSystem InstallationInstallation

46. WATERWATERWATERWATER
I t ll ti Q lifi tiI t ll ti Q lifi ti
TestingTesting
Installation QualificationInstallation Qualification
WeldingWelding isis importantimportant forfor consistentconsistent andand reliablereliable productionproduction ofof
highhigh puritypurity waterwater..
ValidationValidation engineerengineer toto examineexamine logs,logs, MethodMethod utilized,utilized, welderwelderValidationValidation engineerengineer toto examineexamine logs,logs, MethodMethod utilized,utilized, welderwelder
certifications,certifications, inspections,inspections, isometricisometric drawingsdrawings (weld(weld
locations),locations), etcetc.. associatedassociated withwith thethe weldingwelding numbernumber ofof weldswelds
(ANSI(ANSI ZIZI..44)) areare verifiedverified ..(( ))
FiltersFilters areare placedplaced onon storagestorage tanktank ventsvents (hydrophobic)(hydrophobic) toto
precludepreclude airborneairborne contaminationcontamination fromfrom enteringentering thethe highhigh puritypurity
waterwater HydrophilicHydrophilic filtersfilters maymay bebe placedplaced atat pointpoint ofof useuse totowaterwater.. HydrophilicHydrophilic filtersfilters maymay bebe placedplaced atat pointpoint ofof useuse toto
removeremove microbesmicrobes entrainedentrained inin thethe waterwater

47. WATERWATERWATERWATER
I t ll ti Q lifi tiI t ll ti Q lifi ti
PassivationPassivation
Installation QualificationInstallation Qualification
PassivationPassivation
Passivation protects stainless steel piping by inerting thePassivation protects stainless steel piping by inerting thePassivation protects stainless steel piping by inerting thePassivation protects stainless steel piping by inerting the
surface to corrosion.surface to corrosion.

48. WATERWATERWATERWATER
Pi i Sl /P&IDPi i Sl /P&ID
Installation QualificationInstallation Qualification
Piping Slope/P&IDPiping Slope/P&ID
Pharmaceutical piping is installed with a slope of 1/8” per footPharmaceutical piping is installed with a slope of 1/8” per foot
TheThe P&IDsP&IDs areare thethe mostmost importantimportant systemsystem documentsdocuments describingdescribing graphicallygraphically
TheThe systemsystem componentscomponents
InstrumentationInstrumentation
LayoutLayout
TypicalTypical itemsitems foundfound onon thesethese drawingsdrawings areare
StorageStorage tankstanks
PumpsPumpsPumps,Pumps,
PipingPiping
Valves,Valves,
HeatHeat exchangersexchangersgg
PointsPoints--ofof--useuse
SampleSample valvesvalves
InstrumentationInstrumentation..

49. WATERWATERWATERWATER
Piping Slope/P&IDPiping Slope/P&ID
Installation QualificationInstallation Qualification
p g p /p g p /
InstallationInstallation QualificationQualification verifiesverifies ::
ControlControl systemsystem installationinstallation
HydrostaticHydrostatic pressurepressure testingtesting auditsaudits
FilterFilter integrityintegrity testingtesting
P&IDs,P&IDs, utilityutility functionfunction
MajorMajor componentcomponent installationinstallationMajorMajor componentcomponent installationinstallation
CriticalCritical instrumentinstrument installationinstallation..

50. WATERWATERWATERWATER
Installation QualificationInstallation Qualification
Utilities, Equipment and Instrument InstallationUtilities, Equipment and Instrument Installation
UtilitiesUtilities thatthat areare requiredrequired forfor appropriateappropriate andand safesafe systemsystem
QQ
UtilitiesUtilities thatthat areare requiredrequired forfor appropriateappropriate andand safesafe systemsystem
operationoperation mustmust havehave beenbeen installedinstalled andand supplysupply thethe utilityutility
essentialessential forfor waterwater systemsystem operationoperation.. ThisThis meansmeans checkingchecking ofof
FlowsFlows
PressuresPressures
VoltageVoltageo go g
etcetc.. ofof electricalelectrical
CompressedCompressed gasgas (air,(air, inert)inert)
SteamSteamSteamSteam
GlycolGlycol
drainagedrainage systemssystems..

51. WATERWATERWATERWATER
I t ll ti Q lifi tiI t ll ti Q lifi ti
Control System InstallationControl System Installation
Installation QualificationInstallation Qualification
Control System InstallationControl System Installation
ControlControl systemssystems (PLC(PLC.. DCS,DCS, etcetc..)) associatedassociated withwith thethe waterwaterControlControl systemssystems (PLC(PLC.. DCS,DCS, etcetc..)) associatedassociated withwith thethe waterwater
systemsystem mustmust bebe validatedvalidated..

52. WATERWATERWATERWATER
I t ll ti Q lifi tiI t ll ti Q lifi ti
Control System InstallationControl System Installation
Installation QualificationInstallation Qualification
Control System InstallationControl System Installation
TheThe validationvalidation cancan bebe partpart ofof thethe equipmentequipment validationvalidation oror aaTheThe validationvalidation cancan bebe partpart ofof thethe equipmentequipment validationvalidation oror aa
separateseparate controlcontrol systemsystem validation,validation, butbut inin thethe finalfinal analysisanalysis
therethere cancan bebe nono doubtdoubt thatthat thethe integratedintegrated systemsystem provideprovide
securesecure consistentconsistent andand reliablereliable operationoperationsecure,secure, consistentconsistent andand reliablereliable operationoperation..

53. WATERWATERWATERWATER
i l lifi ii l lifi iOperational QualificationOperational Qualification
PrerequisitesPrerequisites toto thisthis phasephase areare thethe successfulsuccessful completioncompletion ofof ananPrerequisitesPrerequisites toto thisthis phasephase areare thethe successfulsuccessful completioncompletion ofof anan
InstallationInstallation Qualification,Qualification, instrumentinstrument calibrationcalibration andand StandardStandard
OperatingOperating ProcedureProcedure (SOP)(SOP)..
TheThe operationaloperational qualificationqualification verifiesverifies controlcontrol systemsystem functionsfunctionsTheThe operationaloperational qualificationqualification verifiesverifies controlcontrol systemsystem functionsfunctions
(I/Os(I/Os normalnormal operations,operations, alarms,alarms, interlocksinterlocks andand security),security),
differentialdifferential pressure,pressure, normalnormal cyclecycle operation,operation, waterwater generationgeneration
(capacity,(capacity, quality)quality) andand waterwater distributiondistribution underunder worstworst casecase(capacity,(capacity, quality)quality) andand waterwater distributiondistribution underunder worstworst casecase
scenariosscenarios.. StandardStandard operatingoperating proceduresprocedures (SOP)(SOP) forfor
calibration,calibration, sanitization,sanitization, operationoperation andand maintenancemaintenance
qualificationqualification areare formalizedformalized duringduring thisthis phasephase..qq gg pp

54. WATERWATERWATERWATER
Operational QualificationOperational Qualification
Integrated Control and Equipment TestingIntegrated Control and Equipment Testing
Operational QualificationOperational Qualification
LocalLocal controlcontrol panelpanel isis testedtested toto verifyverify thethe functioningfunctioning ofof
On/offOn/off switchedswitched
SetSet pointspoints
IndicatoIndicato cont olle scont olle s eco de seco de sIndicator,Indicator, controllers,controllers, recordersrecorders
ForcedForced alarmsalarms
ElectricalElectrical oror mechanicalmechanical interlocksinterlocks
SecuritySecurity onon thethe systemsystem
LossLoss ofof utilitiesutilities testingtesting

55. WATERWATERWATERWATER
i l lifi ii l lifi i
Cycle TestingCycle Testing
Operational QualificationOperational Qualification
y gy g
NormalNormal operationoperation ofof thethe cyclecycle (including(including startup,startup, shutdown,shutdown,
componentcomponent operationoperation andand regenerationregeneration sanitizationsanitization andand looploopcomponentcomponent operationoperation andand regeneration,regeneration, sanitizationsanitization andand looploop
distribution)distribution) isis verifiedverified..
TestingTesting shouldshould bebe donedone onon thethe cyclecycle toto verifyverify thatthat thethegg yy yy
integratedintegrated systemsystem cancan provideprovide thethe specifiedspecified waterwater qualityquality andand
quantityquantity overover thethe longestlongest uninterrupteduninterrupted operatingoperating cyclecycle..
TheThe distributiondistribution systemsystem shouldshould bebe testedtested underunder worstworst casecaseyy
conditionsconditions..

56. WATERWATERWATERWATER
f lifi if lifi iPerformance QualificationPerformance Qualification
TheThe firstfirst partpart ofof thisthis testingtesting isis aa verificationverification ofof distributiondistribution
looploop sanitizationsanitization.. TemperatureTemperature isis recordedrecorded duringduring thethe
sanitizationsanitization atat thethe pump,pump, storagestorage tanktank andand beforebefore thethe heatheatp p,p p, gg
exchangerexchanger..
TheThe finalfinal partpart ofof thethe PerformancePerformance qualificationqualification isis normallynormallyTheThe finalfinal partpart ofof thethe PerformancePerformance qualificationqualification isis normallynormally
preformedpreformed inin threethree operationaloperational phasephase..

57. WATERWATERWATERWATER
f lifi if lifi i
Phase IPhase I
Performance QualificationPerformance Qualification
Phase IPhase I
PhasePhase II cyclecycle developmentdevelopment confirmsconfirms thatthat thethe StandardStandard
operatingoperating proceduresprocedures (SOPs)(SOPs) areare adequateadequate forforoperatingoperating proceduresprocedures (SOPs)(SOPs) areare adequateadequate forfor
SamplingSampling
OperationOperationOperationOperation
MaintenanceMaintenance andand sanitizationsanitization..
TheThe verificationsverifications consistsconsists ofof samplingsampling allall pointspoints ofof useuse (POU)(POU)p gp g pp ( )( )
dailydaily overover aa periodperiod ofof 22--44 weeksweeks ((33 sanitizationsanitization cycles)cycles)..

58. WATERWATERWATERWATER
Phase IIPhase II
Performance QualificationPerformance Qualification
IfIf adjustmentsadjustments oror proceduralprocedural changeschanges areare mademade inin PhasePhase I,I,
hh ll d ld l ifif ii
Phase IIPhase II
PhasePhase IIII cyclecycle developmentdevelopment mustmust verifyverify consistentconsistent waterwater
qualityquality andand quantityquantity viavia furtherfurther dailydaily samplingsampling andand testingtesting forfor
chemistry,chemistry, microbiology,microbiology, etcetc.. atat eacheach pointpoint ofof useuse (POU)(POU) forfor 22--
44 weeksweeks ((33 sanitizationsanitization cycles)cycles)44 weeksweeks ((33 sanitizationsanitization cycles)cycles)..

59. WATERWATERWATERWATER
f lifi if lifi i
Phase IIIPhase III
Performance QualificationPerformance Qualification
PhasePhase IIIIII cyclecycle developmentdevelopment assuresassures longlong termterm ((11 YearYear
d i )d i ) ff ff hh d id i dd
Phase IIIPhase III
duration)duration) performanceperformance ofof thethe waterwater productionproduction andand
distributiondistribution systemsystem undergoingundergoing routineroutine operationsoperations suchsuch asas
filterfilter backwash,backwash, demineralizerdemineralizer regenerationregeneration andand preventativepreventative
maintenancemaintenance proceduresprocedures TheThe samplingsampling scheduleschedule duringduring thethemaintenancemaintenance proceduresprocedures.. TheThe samplingsampling scheduleschedule duringduring thethe
remainingremaining 1111--1212 monthsmonths isis thatthat whichwhich willwill bebe inin effecteffect underunder
normalnormal operatingoperating conditionsconditions..
PhasePhase IIIIII verifiesverifies impactimpact ofof seasonalseasonal variationvariationPhasePhase IIIIII verifiesverifies impactimpact ofof seasonalseasonal variationvariation..

60. WATERWATERWATERWATER
Compliance AssessmentCompliance AssessmentCompliance AssessmentCompliance Assessment

61. WATERWATERWATERWATER
System InspectionSystem InspectionSystem InspectionSystem Inspection
Armed with asArmed with as--built P&IDs, the evaluator should compare thebuilt P&IDs, the evaluator should compare the
drawings to the as built conditions All equipment anddrawings to the as built conditions All equipment anddrawings to the as built conditions. All equipment anddrawings to the as built conditions. All equipment and
instrumentation should have a log, and it should agree withinstrumentation should have a log, and it should agree with
the drawing.the drawing.
During the walkDuring the walk down any dead legs threaded connectionsdown any dead legs threaded connectionsDuring the walkDuring the walk--down, any dead legs, threaded connections,down, any dead legs, threaded connections,
nono--sanitary fittings, system leaks, and nonsanitary fittings, system leaks, and non--drainable pipingdrainable piping
should be noted. The 6D rule limits piping length from theshould be noted. The 6D rule limits piping length from the
distribution loop to the equipment to six times the distributiondistribution loop to the equipment to six times the distributiondistribution loop to the equipment to six times the distributiondistribution loop to the equipment to six times the distribution
piping diameter.piping diameter.
Sampling should be observed with the operator noting when,Sampling should be observed with the operator noting when,
where, and how chemical, microbiological and endotoxinwhere, and how chemical, microbiological and endotoxinwhere, and how chemical, microbiological and endotoxinwhere, and how chemical, microbiological and endotoxin
samples are takensamples are taken

62. WATERWATERWATERWATER
SamplingSamplingSamplingSampling
Sampling should be observed with the operator noting when,Sampling should be observed with the operator noting when,
where, and how chemical, microbiological and endotoxinwhere, and how chemical, microbiological and endotoxin
samples are takensamples are taken

63. WATERWATERWATERWATER
il & i iil & i iFailure Reports & InvestigationsFailure Reports & Investigations
Chemical, microbiological and endotoxin analysis data for theChemical, microbiological and endotoxin analysis data for the
last two years should be reviewed and any trends noted.last two years should be reviewed and any trends noted.

64. WATERWATERWATERWATER
Failure Reports & InvestigationsFailure Reports & Investigations
Failure investigations and corrective actions should have beenFailure investigations and corrective actions should have been
timely and technically adequate.timely and technically adequate.

65. WATERWATERWATERWATER
i f Ch i l / i bi l i l i ii f Ch i l / i bi l i l i iReview of Chemical / Microbiological Monitoring programReview of Chemical / Microbiological Monitoring program

66. WATERWATERWATERWATER
i d l b li d l b lAction and Alert LabelsAction and Alert Labels

67. WATERWATERWATERWATER
Protocol reviewProtocol reviewProtocol reviewProtocol review

68. WATERWATERWATERWATER
SummarySummary
ValidationValidation ofof aa waterwater systemsystem consistsconsists ofof
verifyingverifying installation,installation, operationoperation andand
performanceperformance.. TheThe qualificationsqualifications assuresassures thatthat thethepp qq
waterwater systemsystem cancan consistentlyconsistently andand reliablyreliably
produceproduce thethe qualityquality andand quantityquantity ofof highhigh puritypurity
waterwater requiredrequired bebe thethe pharmaceuticalpharmaceutical processprocess oror
d td tproductproduct..

69. Thank you