pharmaceutical water-zahid ali baig

8/14/2019 Pharmaceutical Water-Zahid Ali Baig

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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/


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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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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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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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