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 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
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
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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Iron Removal Plant
Purified Water Plant
Softened Water Plant
Boiler Feed water
Gen. Cooling Water
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
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
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
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
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
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
Latest technological experience delivers complete solutions that meet and exceed
these standards through compliance with:
Latest USP and Ph. European standards
GMP validation control systems
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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1. Edstrom Industries (www.edstrorm.com)
2. Water Quality Association (WQA) 1998
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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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