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Pharmaceutical Water Systems
Zahid Ali Baig Sante (Pvt) Limited
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WATERis most widely used and sometime mostexpensive substance as raw material or ingredientin Pharmaceuticals;
Production
Processing Formulation
Cleaning
Pharmaceutical waters used in the manufacture of
drugs or drug products are subject to the regulations of
the cGMPs whether or not the water remains in the finalproduct
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TYPES OF WATERTYPES OF WATER
USP differentiate between various types of water:
Drinking Water : Non Compendial but must complywith requirements of EPA. Used as feed water for the
production of Pharmaceutical water
Purified Water (PW) : Must meet the ionic andorganic purity and protected from microbial
proliferation. Used in production of oral products,
pharmaceutical application and bulk pharmaceuticals
Water for Injection (WFI): Must meet the chemicalrequirements of PW and in addition Bacterial
Endotoxin and microbial contaminations.
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USP Specifications in PracticeUSP Specifications in Practice
Purified waterPurified waterused for non-injectable drugs can accept aused for non-injectable drugs can accept a
small amount of microbial contaminationsmall amount of microbial contamination and hasand has nonospecifications on endotoxin.
specifications on endotoxin.
WFIWFI used for injectable drugs are expected to beused for injectable drugs are expected to be free fromfree from
micro organismsmicro org
anisms but since some micro organisms may bebut since some micro organisms may beencountered during sampling, an action limit of 10 CFU/100encountered during sampling, an action limit of 10 CFU/100
ml is commonly specified.ml is commonly specified.
In WFIIn WFI endotoxin are a concernendotoxin are a concern and if bacteria areand if bacteria are
introduced to the system and killed, these bacteria willintroduced to the system and killed, these bacteria will
release endotoxin. Therefore, strict measurement has to berelease endotoxin. Therefore, strict measurement has to be
taken not to introduce any bacteria into the system and totaken not to introduce any bacteria into the system and to
secure that the small amount of bacteria in the system hassecure that the small amount of bacteria in the system has
no possibility to grow.no possibility to grow.
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Basis of Water Selection on the Needs ofBasis of Water Selection on the Needs of
the processthe process
the productthe product
the specific applicationthe specific application
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Surface or ground waterSurface or ground water Well or boreholeWell or borehole
Municipal or civil tap waterMunicipal or civil tap water
Tanker Water ?Tanker Water ?
Source of Raw Water
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Contaminants of waterContaminants of water
There is noThere is no pure waterpure waterin nature, as it can contain up toin nature, as it can contain up to9090 possible unacceptable contaminants:possible unacceptable contaminants:
Contaminant groups:Contaminant groups: Inorganic compoundsInorganic compounds
Organic compoundsOrganic compounds
SolidsSolids
GasesGases
Micro-organismsMicro-organisms
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Why purify raw waterWhy purify raw water??
To remove impurities to prevent product contamination.To remove impurities to prevent product contamination.
To control microbes to avoid contaminating productsTo control microbes to avoid contaminating products
To avoid seasonal variations in raw waterTo avoid seasonal variations in raw water
To remove regional impurities from poor quality waterTo remove regional impurities from poor quality water
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Pre Treatment StepsPre Treatment Steps
Primary filtration and multi-media filterPrimary filtration and multi-media filter
Coagulation or flocculationCoagulation or flocculation
DesalinationDesalination
SofteningSoftening
ChlorinationChlorination
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raw water in
S trap to sewer
Water is keptcirculating
To watersoftener &
DI plant
Pretreatment schematic
drawing
cartridgefilter
5 micrometers
activatedcarbonfilter
spray ball
break tank
air break to draincentrifugal pump
air filter
floatoperated
valvesand filter
excess water recycledfrom deioniser
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DRINKING WATER
EPA Quality
Typical Treatment Steps
* Softening * Reverse Osmosis
* Dechlorination * Ultrafiltration
* Deionization * Distillation
PURIFIED WATER USP
DISTILLATION OR
REVERSE OSMOSIS
WATER FOR INJECTION
Major components for Pharmaceutical WatersMajor components for Pharmaceutical Waters
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Pharmaceutical WatersPharmaceutical Waters
Purified WaterPurified Water Obtained by distillation, ion-exchange treatment,Obtained by distillation, ion-exchange treatment,
reverse osmosis, or other suitable process;reverse osmosis, or other suitable process;
Prepared from water complying with the regulations ofPrepared from water complying with the regulations of
the federal Environmental Protection Agency (EPA) withthe federal Environmental Protection Agency (EPA) with
respect to drinking water;respect to drinking water;
Contains no added substancesContains no added substances
Water for InjectionWater for Injection
Water for Injection (WFI) is water purified by distillationWater for Injection (WFI) is water purified by distillationor by reverse osmosis that contains no addedor by reverse osmosis that contains no added
substances.substances.
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USP Specifications: PW vs. WFI
PW (PurifiedWater)
WFI (Water forInjection)
Water conductivityand pH
< 1,3 S/cm at25C* pH 5-7
< 1,3 S/cm at 25C*pH 5-7
Total OrganicCarbon (TOC) < 0.5 ppm < 0.5 ppm
Aerobic Microbial
Contamination
< 100 CFU/ ml < 10 CFU/100 ml(
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raw water
High pressure
Feed
water
under
pressure
Re
ject
wate
r
Se
mi-p
erm
eab
le
me
mb
ran
e
Pe
rmeate
wate
r
drain or recycle
Low pressure
Purified water
REVERSE OSMOSIS
Reverse osmosis may beused to:
purified water
feeding of distillation unitsor ultra-filtration units
water for final rinse
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REVERSE OSMOSIS
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RO System
http://www.pharmaceutical-technology.com/contractors/water_treatment/puretech/8/14/2019 Pharmaceutical Water-Zahid Ali Baig
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Feed
water
Reverse
osmosis
Electro-
deionisation Tank
Distillation system
Tank
Water purification & distribution loop
Purification process
Distribution loop
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Water for Injection (WFI) DistillationWater for Injection (WFI) DistillationTechniqueTechnique
Vapor Compression (VC)Vapor Compression (VC) Uses plant steam to convert initial feedwater toUses plant steam to convert initial feedwater to
vapor (pure steam)vapor (pure steam)
Pure steam is compressed, elevatingPure steam is compressed, elevating
temperaturetemperature Compressed vapor is used to evaporate newCompressed vapor is used to evaporate new
feedwater, giving up latent heat andfeedwater, giving up latent heat andcondensing as WFIcondensing as WFI
Higher electrical demand, but lower steamHigher electrical demand, but lower steam
demanddemand
f ( )
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Water for Injection (WFI) Distillation TechniqueWater for Injection (WFI) Distillation Technique
Multi-Effect Still (MES)Multi-Effect Still (MES)
Uses Plant Steam to convert feedwater to pure steamUses Plant Steam to convert feedwater to pure steam
Separators allow impurities to drop out of the pure steamSeparators allow impurities to drop out of the pure steam
Pure steam from first effect used to convert feedwater toPure steam from first effect used to convert feedwater topure steam in subsequent effectspure steam in subsequent effects
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Bacteria in Pharmaceutical water systemsBacteria in Pharmaceutical water systems
The most common bacteria in water system isThe most common bacteria in water system isPseudomonas sps. which can tolerate a maximumPseudomonas sps. which can tolerate a maximumtemperature of 45temperature of 45CC
In rare cases Pathogens could be found. These canIn rare cases Pathogens could be found. These cantolerate a maximum temperature of 55Ctolerate a maximum temperature of 55C
Mesophile bacteria have ionophores helping them collectMesophile bacteria have ionophores helping them collectand store minerals and thus have the potential to liveand store minerals and thus have the potential to liveand grow in pharmaceutical water systemsand grow in pharmaceutical water systems
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Development of biofilm in water pipes and tanks is anothercommon source of endotoxin. Biofilm is an accumulation of
microbes (dead and live) on pipes and surfaces, particularly
near joints, elbows or dead legs. This film is removed by
high shearing forces or with chemical substances.
In order to grow in nature or in the laboratory, a bacterium
must have an energy source, a source of carbon and other
required nutrients, and a permissive range of physicalconditions such as O
2concentration, temperature, and pH.
Bacteria in Pharmaceutical waterBacteria in Pharmaceutical water
systemssystems
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SanitizationSanitization
Aerobi c
Micro
bial
Contaminatio
nC
FU
/ml
Endoto
xinEU
/ml
Time
Acceptance limit EU/ml
Bacteria and Endotoxin growth in ambient water system
Acceptance limit CFU/ml
Sanitization Sanitization
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Storage and DistributionStorage and Distribution
These can be divided in 3 different temperature
types:
Hot water systems (self sanitised)
Ambient water systems (needs sanitization)
Cold water systems (needs sanitization)
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T
Steam
Cond.
Hot
Storage
Tank
Control Valve
(optional)
Most Advantageous When:Hot water is requiredHot water is generated
Microbial control is critical
Least Advantageous When:Ambient temperature water
required
Hot Storage, Hot DistributionHot Storage, Hot Distribution
A bi S A bi Di ib iA bi t St A bi t Di t ib ti
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NOTE: Identical configuration for Cold Storage, Cold Distribution System
Control Valve
Coolant
Coolant
Ambient
Storage
Tank
Sanitizing /Cooling
Heat Exchanger
T
Cond.
Steam
(optional)
Coolant
Coolant
Most Advantageous When:High peak demands for ambient or cold waterWater is generated at ambient temperatureThere is adequate time for sanitization
Least Advantageous When:Sanitization will not fit into
operating schedule
Ambient Storage, Ambient DistributionAmbient Storage, Ambient Distribution
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Storage and Distribution
contact materialscontact materials
Factors to consider (including components)Factors to consider (including components)
Compatibility and leaching effectCompatibility and leaching effect
Corrosion resistanceCorrosion resistance
Smooth internal finishing, ease of jointingSmooth internal finishing, ease of jointing
Hygienic / sanitary designHygienic / sanitary design
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Water system contact materialsWater system contact materials
CompatibilityCompatibility With temperature and chemicals used in theWith temperature and chemicals used in thesystemsystem
Leaching effectLeaching effect
Non-leaching at temperature rangeNon-leaching at temperature range Corrosion resistanceCorrosion resistance
Stainless steel Grade 316L to be usedStainless steel Grade 316L to be used
System passivated after installation andSystem passivated after installation and
modification according to SOPmodification according to SOP
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Water system contact materialsWater system contact materials
Suitable materials include:Suitable materials include: Stainless steel Grade 316 & 316LStainless steel Grade 316 & 316L
Polypropylene (PP)Polypropylene (PP)
Polyvinylidenedifluoride (PVDF)Polyvinylidenedifluoride (PVDF)
Perfluoroalkoxy (PFA)Perfluoroalkoxy (PFA) Teflon, Silicone, Viton (gaskets, diaphragms)Teflon, Silicone, Viton (gaskets, diaphragms)
Unplasticized polyvinylchloride (uPVC) used forUnplasticized polyvinylchloride (uPVC) used fornon-non-hygienichygienicdesigned water treatment equipment suchdesigned water treatment equipment suchas ion exchangers and softenersas ion exchangers and softeners
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Water system contact materialsWater system contact materials
Smooth internal finishSmooth internal finish
Biofilms and microbial contaminationBiofilms and microbial contamination
Crevices and roughness result in problem areasCrevices and roughness result in problem areas
associated with contamination and corrosionassociated with contamination and corrosion
Mechanical and electro-polishing needed whenMechanical and electro-polishing needed when
stainless steel is usedstainless steel is used
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Validation StrategyValidation Strategy
a.a. Design/installation reviewDesign/installation review
b.b. SOP development and confirmationSOP development and confirmation
c.c. Demonstration and effectivenessDemonstration and effectiveness
d.d. Data compilation and sign offData compilation and sign off
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V-Model Direct Impact SystemsV-Model Direct Impact Systems
ISPE Baseline Guides Volume 5: Commissioning and Qualification March 2001
URS
FS
DS IQ
OQ
PQ
Commissioning Qualification
Implementation
ValidationPQ Test Plan
IQ Test Plan
(incl. PDI)
OQ Test Plan
(incl. FAT)
Impact assessment
PDI: Pre Delivery Inspection
FAT SAT
Process Validation Cleaning Validation Revalidation
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IQ /OQIQ /OQ
IQ should involve the identification of all system elements, serviceIQ should involve the identification of all system elements, serviceconduits/pipes and gauges and the preparation of a documentedconduits/pipes and gauges and the preparation of a documentedrecord that all installed equipments satisfies the plannedrecord that all installed equipments satisfies the plannedrequirements.requirements.
Identification and documenting of preventative maintenance andIdentification and documenting of preventative maintenance andgeneral maintenance requirementsgeneral maintenance requirements
OQ is the studies of the critical variables of the operation of theOQ is the studies of the critical variables of the operation of theequipment or systems and will define the critical characteristics forequipment or systems and will define the critical characteristics foroperation of the system or sub-systemoperation of the system or sub-system
It is important to assure that all operational test data conform withIt is important to assure that all operational test data conform withpre-determined acceptance criteriapre-determined acceptance criteria
After OQ it should be possible to finalise the operating proceduresAfter OQ it should be possible to finalise the operating procedures
and operator instructions documentationand operator instructions documentation
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Validation, Documentation and SOPsValidation, Documentation and SOPs
Validation means documented evidence that theValidation means documented evidence that thesystem function as designed, in a consistent andsystem function as designed, in a consistent and
effective manner, and in accordance to predeterminedeffective manner, and in accordance to predetermined
criteria.criteria.
Validation demonstrates that there is a high probabilityValidation demonstrates that there is a high probabilityof an acceptable outcome if the system is operated inof an acceptable outcome if the system is operated in
the same way as when it was validatedthe same way as when it was validated
To demonstrate consistency and continuing properTo demonstrate consistency and continuing properoperation, continuingly effective cleaning practicesoperation, continuingly effective cleaning practices
and routine monitoring should be applied, SOPsand routine monitoring should be applied, SOPs
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SUMMARYSUMMARY
The water distribution system is a rather unique systemThe water distribution system is a rather unique systemin the pharmaceutical industryin the pharmaceutical industry
It is a continuous system (no batch manufacturing)It is a continuous system (no batch manufacturing)
The product (water) is extremely clean and free fromThe product (water) is extremely clean and free fromnutrient and mineralsnutrient and minerals
It is a closed systemIt is a closed system
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The main concerns for water systems areThe main concerns for water systems are::
Try to keep it as a continuous and closed loopTry to keep it as a continuous and closed loop
Dont disturb itDont disturb it
There should be no risk of stains or residue in the systemThere should be no risk of stains or residue in the system
Bacteria will however generate biofilm and this is the mainBacteria will however generate biofilm and this is the mainconcernconcern
SUMMARYSUMMARY
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