SUMMARY

The requirement for water quality varies from industry to industry so does the

treatment methods. Available water treatment systems in pharmaceutical industries

have been discussed briefly along with the system components to give information

about water purification leading to USP grade purified water. Pharmaceutical

industries make use of the advanced technology to generate maintain and monitor

water quality conforming to the international standards. Water may be contaminated

in various ways with different pollutants. Water systems also monitor for a number of

contaminants that are currently not regulated. This monitoring data provides the basis

for identifying contaminants to be regulated in the future. The amount and type of

treatment varies with the source type and quality. Many ground water systems can

satisfy all requirements without applying any treatment, while others need additional

treatment. Water suppliers use a variety of treatment processes to remove

contaminants from drinking water. The most commonly used processes include

filtration, flocculation and sedimentation, and disinfections for surface water. Some

treatment trains also include ion exchange and adsorption. Water utilities select a

combination of treatment processes most appropriate to treat the contaminants found

in the raw water used by the system. The purpose of this report is to provide

information on water purification systems ( generation of water ) regarding their use

in the Pharmaceutical industries concerning water quality requirement specified by

USP and regulatory bodies for pharmaceutical process and other applications.

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IntroductionWithin the pharmaceutical industry, water is most commonly used in liquid form, not

only as an ingredient in many formulations but also as a cleaning agent. Production of

Purified Water, Highly Purified Water, Pyrogen Free Water and WFI to international

pharmaceutical standards is widely recognized as a critical process.

Water is a very important element in our everyday life. Ranging from

household to industry; water is utilized for various purposes. However, water is

contaminated with different pollutants from its source in many ways including

microorganisms. By using different water treatment methods, water can be purified as

per specific requirement. Water quality requirement for a pharmaceutical industry is

of utmost importance to formulate quality medicines having no adverse health effects.

Water sources

Water is generally classified into two groups: Surface Water and Ground Water.

Surface water is found in a river, lake or other surface impoundment. This water is

usually not very high in mineral content, and many times is called "soft water" even

though it usually is not. Surface water is exposed to many different contaminants,

such as animal wastes, pesticides, insecticides, industrial wastes, algae and many

other organic materials. Even surface water found in a pristine mountain stream

possibly contains Giardia or Coliform Bacteria from the feces of wild animals, and

should be boiled or disinfected by some means prior to drinking.

Ground Water is that which is trapped beneath the ground. Rain that soaks

into the ground, rivers that disappear beneath the earth, melting snow are but a few of

the sources that recharge the supply of underground water. Because of the many

sources of recharge, ground water may contain any or all of the contaminants found in

surface water as well as the dissolved minerals it picks up during it's long stay

underground. Waters that contains dissolved minerals, such as calcium and

magnesium above certain levels are considered "hard water" Because water is

considered a "solvent", i.e., over time it can break down the ionic bonds that hold

most substances together, it tends to dissolve and 'gather up' small amounts of

whatever it comes in contact with. For instance, in areas of the world where rock such

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as limestone, gypsum, fluorspar, magnetite, pyrite and magnesite are common, well

water is usually very high in calcium content, and therefore considered "hard".

Necessity of water Treatment

Following are the reasons for water treatment:

To eliminate possible health and environmental hazards

To get safe potable and domestic use water for humans

To get soft water for industrial machinery such as boiler, generator

To get de-mineralized or purified water for manufacturing process

To produce water as per specific requirement

1. Raw Water Treatment Processes

The amount and type of treatment varies with the source type and quality. Many

ground water systems can satisfy all requirements without applying any treatment,

while others need to add chlorine or additional treatment. Because surface water

systems are exposed to direct wet weather runoff and to the atmosphere and are

therefore more easily contaminated, these water should be treated.

Water suppliers use a variety of treatment processes to remove contaminants

from drinking water. These individual processes may be arranged in a "treatment

train" (a series of processes applied in sequence). The most commonly used

processes include filtration, flocculation and sedimentation, and disinfection for

surface water. Some treatment trains also include ion exchange and adsorption.

Water utilities select a combination of treatment processes most appropriate to treat

the contaminants found in the raw water used by the system.

2. Water for Pharmaceutical Process

Pharmaceutical process water should meet the USP requirement for purified water.

Purified Water is described in the USP 23 monograph as follows:

"Purified Water is water obtained by distillation, ion-exchange treatment, reverse

osmosis, or other suitable process. It is prepared from water complying with the

regulations of the U.S. Environmental Protection Agency (EPA) with respect to

drinking water. It contains no added substances."

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Purified water should have the following microbial quality as well as chemical quality

2.1. Microbial Quality

Regarding the bacteriological purity of PW, the monograph states only that PW must

comply with the EPA regulations for drinking water. The EPA regulations only

specify limits for coliform bacteria. In the informational section of the USP 23, which

deals with action guidelines for the microbial control of ingredient water, it says:

"A total microbial (aerobic) count that may be used for source drinking water is 500

colony-forming units (cfu) per mL. A general guideline for Purified Water may be 100

cfu/mL."

These numbers for cfu/mL are only advisory guidelines that represent

recommended alert/action limits, not reject levels. The informational section also

suggests that the microbial action limits for PW should be based on the intended use

of the water and the nature of the product being made. It recognizes that microbial

limits for PW require being defined on a case-by-case basis.

USP23 Supplement 5, effective since November 1996, specifies the method for total

bacteria counts. It states "Heterotrophic Plate Count of a 1-mL sample, using Plate

Count Agar at an incubation temperature of 30 to 35 degrees Celsius for a 48-hour

period (minimum)." There is some controversy (Collentro 1996) because this method

will underestimate "starved" bacteria in high-purity water.

2.2. Chemical Quality

Effective November 15, 1996, the former inorganic chemistry tests (for calcium,

sulfate, chloride, ammonia, and carbon dioxide) were replaced with a three stage

conductivity test. The conductivity limit is pH dependent, but for example, at pH 7.0,

conductivity should be less than 5.8 microSiemens/cm. The former test for oxidizable

substances was replaced with a Total Organic Carbon (TOC) limit of 0.05 mg/L. TOC

is an indirect measure of organic molecules present in water measured as carbon. The

new tests allow continuous in-line monitoring of water using instrumentation rather

than lab work.

3. Water For Injection (WFI)

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The USP 23 monograph states:

"Water for Injection (WFI) is water purified by distillation or reverse osmosis."

WFI is produced by either distillation or 2-stage RO. It is usually stored and

distributed hot (at 80 degrees C) in order to meet microbial quality requirements.

3.1. Microbial Quality

The USP monograph makes no references to bacteria limits for WFI. It does not need

to be sterile; however, the monograph specifies that WFI not contain more than 0.25

USP endotoxin units (EU) per mL. Endotoxins are a class of pyrogens that are

components of the cell wall of Gram-negative bacteria (the most common type of

bacteria in water).

They are shed during bacterial cell growth and from dead bacteria. Indirectly,

the water must be of a very high microbial quality in order to have a low endotoxin

concentration. The USP informational section recommends an action limit of 10

cfu/100 mL. The recommended method of testing is membrane filtration of a 100-mL

sample and plate count agar at an incubation temperature of 30 to 35 degrees Celsius

for a 48-hour period.

3.2. Chemical Quality

The chemical purity requirements of WFI are the same as PW (purified water). 

4. Modern Water Treatment Processes in Pharmaceutical Industries

In Pharmaceutical Industries, raw water is treated in different stages to meet criteria

specified for various applications. Process water should meet USP specification for

purified water. Besides soft water is used for boiler feed water and generator cooling

tower. Pre-treated water is used for drinking, sanitary, washing applications etc.

Water treatment system consists of the following four plants:

Iron Removal Plant

Pre-Treatment Plant

Softened Water Plant

Purified Water Plant

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A block diagram showing all the plants is given below:

Figure 01: Block Diagram of water treatment plants

4.1 Iron Removal Plant

Bore hole water is passed through Deep tube well to Iron Removal Plant. Iron is

removed here with the help of Sand filter. Alum is dosed to the raw water prior to

entrance to the sand filter. Required Iron concentration is less than 0.1 ppm.

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Bore Hole

Iron Removal Plant

Pre-treatment Plant

R.C.C Tank

Purified Water Plant

Softened Water Plant

Boiler Feed water

Gen. Cooling Water

Closed Loop

distri-

bution

User Points

Water for Domestic use

PW plant and distilled water plant

4.2 Pre-Treatment Plant

This plant consists of tank, pumps, sand filters, activated carbon filters and dosing

systems. Raw water pump takes water from the tank and forces through the filtration

media of the Omnifiltration system. Flocculant such as alum is dosed to destabilize

the colloidal particles and to give rise to insoluble compounds before entry to the

filtration media. Omnifiltration system consists of two filters installed in series and

controlled by diaphragm valves. Water passes downwards through the filtering layers

in the two units and flows out of system free of particulate material or undesirable

elements. Sodium hypochlorite is dosed for oxidization as well as for minimizing

microbiological contamination. Activated carbon filters remove color, odor and free

chlorine.

4.3 Softened Water Plant

Hardness in a water supply can result in scale formation, which is a deposit of

minerals left over after the water has been removed or evaporated. This can be

foundin reverse osmosis systems, clean steam generators and distillation systems.

The most common technology used for removing scale formed by calcium and

magnesium ions is ion exchange water softening. A water softener has four major

components, a resin tank, resin, a brine tank and valves or controller. When hard

water is passed through the resin, calcium, magnesium, and other multivalent ions

such as iron adheres to the resin, releasing the sodium ions until equilibrium is

reached. A regeneration is needed to exchange the hardness ions for sodium ions by

passing a sodium chloride (NaCl) solution (called brine) through the resin.

Acidification/Degasification can be used as a softening process but it has

numerous disadvantages, such as handling chemical (sulphuric acid, anti-scalant) and

instrumentation for two Ph adjustments. Nanofiltration is sometimes referred to as a

softening membrane process and will remove anions and cations. The feedwater

requirement for a nanofiltration system is about the same as for a reverse osmosis

system and feed water should be pre-treated prior to going to the membranes.

4.4 Purified Water Plant

Purified Water is generated by Reverse Osmosis (RO) and continuous De-ionization

(CDI). Softened water is passed through a packaged water treatment unit called

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Ionpro plus that consists of Reverse Osmosis and continuous di-ionization system.

This unit runs continuously to fill the purified water storage tank of capacity 10000

liters. The treated water from the unit passes through a UV sterilizer to control

microbial contamination. The purified water from the storage tank is pumped through

the ring main via heating and cooling exchangers to different user points. Vessel and

pipe work are constructed from SS316L. The plant has a PW capacity of 550 lts/hr.

The USP grade of Purified Water are PH=5.7, TOC< 500 ppb, Microbial Content

≤100 cfu/ml and conductivity < 1.3µs/cm.

4.4.1. Reverse Osmosis stage

RO membranes are used to remove contaminants that are less than 1 nm nominal

diameter. Reverse osmosis typically removes 90% to 99% of ionic contamination,

most organic contamination, and nearly all particulate contamination from water. RO

removal of non-ionic contaminants with molecular weights <100 Dalton can be low.

It increases at higher molecular weights and, in theory, removal will be complete for

molecules with molecular weights of >300 Dalton and for particles, including colloids

and micro-organisms. Dissolved gases are not removed (eg. CO2).

During reverse osmosis, pretreated water is pumped past the input surface of

an RO membrane under pressure (typically 4-15 bar, 60-220 psi) in cross-flow

fashion. RO membranes are typically thin film composite (polyamide). They are

stable over a wide pH range, but can be damaged by oxidizing agents such as

chlorine, present in municipal water. Pretreatment of the feedwater with microporous

depth filters, softener and activated carbon is usually required to protect the

membrane from large particulates, hardness and free chlorine. Typically 75%-90% of

the feedwater passes through the membrane as permeate and the rest exits the

membrane as concentrate, that contains most of the salts, organics, and essentially all

of the particulates. The ratio of the volume of permeate to the volume of feedwater is

referred to as the "recovery". Operating an RO system with a low recovery will

reduce membrane fouling, especially that due to precipitation of low solubility salts.

However, recoveries of up to 90% are possible, depending on the quality of the

feedwater and the use of filtration and softening pretreatment.

The performance of the RO component of a water purification system is

typically monitored by measuring the percent ionic rejection, which is the difference

between the conductivities of the feed and permeate divided by the feed conductivity,

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calculated as a %. The "ionic rejection" and "recovery" will vary with the feedwater,

the inlet pressure, the water temperature and the condition of the RO membrane.

Due to its exceptional purifying efficiency, reverse osmosis is a very cost-effective

technology for the removal of the great majority of impurities. Reverse osmosis

protects the system from colloids and organic fouling. It is often followed by ion

exchange or electrodeionisation. Reverse osmosis units need periodic cleaning &

sanitisation with acid and alkaline solutions. Specially constructed membranes are

available for hot water sanitisation at 85¡ÆC.

RO technology involves using a high pressure pump to force a portion of feed

water through a semi-permeable membrane. The amount of permeate product water

produced varies directly with the feed water pressure and temperature. Since the bulk

of the product water contaminants are left on the feed water upstream side of the

membrane and could foul the membrane, a portion of feed water is directed to drain.

This stream is called reject water. An internal pump boosts the feed water to 20 bar

causing water to be foced through the membrane. This results in the removal of

greater than 99% of all micro-organisms, pyrogens, particles, colloids and organics

greater than 200 molecular weight. The ionpro plus unit is supplied with 4 RO

membranes which will deliver upto 550 liters per hour at 20 C. After the RO stage,

the permeate is fed to the CDI stage.

4.4.2. Continuous Electro deionization

Continuous electrodeionization is a technology combining ion exchange resins and

ion-selective membranes with direct current to remove ionised species from water. It

was developed to overcome the limitations of ion exchange resin beds, notably the

release of ions as the beds exhaust and the associated need to change or regenerate the

resins.

Reverse osmosis permeate passes through one or more chambers filled with

ion exchange resins held between cation or anion selective membranes. Ions that

become bound to the ion exchange resins migrate from the dilute chamber to a

separate chamber (concentrate) under the influence of an externally applied electric

field, which also produces the H+ and OH- necessary to maintain the resins in their

regenerated state. Ions in the concentrate chamber are recirculated to a break tank or

flushed to waste.

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The ion exchange beds in continuous electrodeionisaton (CEDI) systems are

regenerated continuously, so they do not exhaust in the manner of ion exchange beds

that are operated in batch mode (with chemical regeneration). CEDI beds are typically

also smaller and remain in service for much longer periods.

CEDI is preferred for many purified water generation applications in Pharma, because

of its "clean" non-chemical nature and constant high quality water produced. 

The resins used in CEDI systems can either be separate chambers of anion or cation

beads, layers of each type within a single chamber or an intimate mixture of cation

and anion beads.

Veolia Water Solutions & Technologies' pharmaceutical CEDI process utilizes

cation beads in the concentrate stream and layered beds of cation and anion resins in

dilute stream.

The resins are housed in wide cells that provide a flow path for the ions in

transit. This offers advantages in the flexibility of design and mechanical simplicity

on an industrial scale. The ion migration from dilute to concentrate is enhanced by the

layered resin bed in the dilute.

Reverse osmosis (and sometimes membrane degassing) is typically used

before CEDI to ensure that the CEDI "stack" is not overloaded with high levels of

salts. The small volume of resins in the stack results in low bleed of organic

molecules. Typically, RO removes about 95% of ions; CEDI will remove 99% of the

remaining ions as well as carbon dioxide, organics and silica.

5. Water for Injection (WFI) Plant

Water for injection is generated by means of multistage (3 rd effect) thermal distillation

with a capacity of 600 liters/hour at atmospheric pressure. Purified water enters to the

first column through a preheating unit. Industrial steam is supplied to the 1st effect

column to generate steam from purified water, which is passed to the second effect

column. Steam from 2nd effect column is passed through the 3rd effect column to

produce purified steam which is condensed and stored in a 4000 liter storage tank as

water for injection.

The design of these units allows producing sterile and pyrogen free water as

defined by the European pharmacopeia and USP standard.

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WFI is maintained at temperature between 80-900C in the storage tank and in

the ring main. Periodic Sterilization of the WFI tank and ring main is performed by

raising the temperature to 1210C and maintaining the temperature for 30 minutes.

The storage tank, pump and ring main have been constructed from Stainless Steel 316L

Figure 02: Flow diagram of purified water and WFI generation

5.1 Key criteria for Purified water (PW) & Water for injection (WFI) Loops

No stagnant conditions and areas of low flow rate

Temperature control

Continuous and turbulent flow at all points in the distribution loop

Proper slope of the pipeline to ensure drainability

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Stainless steel surface finish with appropriate roughness in order to avoid

nutrient and biofilm accumulation

Air breaks

System fully drainable

No deadlegs according 6D rule (CFR 212)

Periodic sanitisation or sterilisation of the storage tank and loop

Storage tank protected with 0.2 micron hydrophobic vent filter

PW & WFI distribution designed as loop configuration

Sufficient instrumentation and monitoring equipments. Critical ones will be

commissioned and qualified

Conclusion

Latest technological experience delivers complete solutions that meet and exceed

these standards through compliance with:

Latest USP and Ph. European standards

cGMP requirements

GMP validation control systems

FDA requirements

ISPE Engineering Guide

IPCC environmental requirements

Whatever our needs - Pre-treatment, Purification, Storage and Distribution of water

- latest Technologies uses the latest technologies available to improve manufacturing

efficiency and reduce costs, without compromising process security and product

quality. All aspects of our product development, project management and service

offerings are managed to a high quality standard to ensure that our dedicated team of

experts is in tune with the market needs.

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Referencess

1. Edstrom Industries (www.edstrorm.com)

2. Water Quality Association (WQA) 1998

3. www.veoliawaterst.com

4. www.microbix.com/products/WFI.html

5. www.honeyman.co.uk

6. www.labx.com

7. www.tka.de

8. www.wfiglobal.com/news/pr/2003-12-29-china.asp

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Probable questions on Water Treatment

1.What are the necessities of water treatment?

2.What are the monographs of purified water?

3.Diagramatically represent the modern water treatment processes used in pharmaceutical industries.

4.Describe the reverse osmosis process for purified water

5.Depict the flow diagram of purified water and WFI generation.

6.What are key criteria for purified water and water for injection (WFI)

7.What are the quality requirements for WFI?

8.What do you know about softened Water Plant?

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