Water Treatment
Dr. Majed Feddah
Pharmaceutical Dosage
Forms and Calculations
Drinking Water
Clear, colorless, odorless, neutral,
Chlorides
Sodium,
The use in pharmaceutical industries
2
Why Purification of Water
1.
Although reasonably pure, it is always variable.
2.
Seasonal variations may occur in water.
3.
Some regions have very poor quality water.
4.
Must remove impurities to prevent product
contamination.
5.
Control microbes to avoid contaminating
products
3
Why Purification of Water
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There is no pure water in nature, as it can
contain large no of possible unacceptable
contaminants
Contaminant groups:
1. Inorganic compounds
2. Organic compounds
3. Solids
4. Gases
5. Micro-organisms
4
Contamination in Water
Problem minerals
1.
2.
3.
4.
5.
6.
Calcium and magnesium
Iron and manganese
Silicates
Carbon dioxide
Hydrogen sulfide
Phosphates
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Contamination in Water
Further problem minerals
1. Copper
2. Aluminum
3. Heavy metals

4.
Arsenic, lead, cadmium
Nitrates
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Microbial Contamination
Micro-organisms – Biofilm
1. Algae
2. Protozoa
 Cryptosporidium
 Giardia
3. Bacteria
 Pseudomonas
 Gram negative, non-fermenting bacteria
 Escherichia coli and coliforms
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Pyrogens and endotoxins

Any compound injected into mammals
which gives rise to fever is a “Pyrogen”.
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Water Types:
There are essentially four types of water that are of
interest to the pharmaceutical industry:
1) Potable water: Feed water, public water supply, service water,
city water, drinking water, National Primary Drinking Water
2) Purified water: Aqua purificata, demineralized water,
deionized water.
3) Water for injection: Aqua ad iniectabilia, ultra pure water,
distilled water
4) Highly purified water: Aqua valde purificata, low endotoxin
water, reverse osmosis water
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Purified Water filled into containers (Packaged
Purified Water)
If purified water is filled into containers for dispensing, it
is a final product.
In this case, additional tests for purity must be carried out.
Purified water filled in containers must also pass the
following tests:
1. Test for acidic or alkaline substances, oxidizable
substances, chlorides, sulfates, ammonium.
2. Microbial purity.
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Application of purified water in bulk
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Manufacturing for category 2, 3 and 4 products
Manufacturing of WFI.
Manufacturing of highly purified water.
Cleaning of facilities.
Cleaning of containers for category 2, 3 and 4 products.
Rinsing of equipment & containers for category 1
products*
Autoclave cooling (only cooling jacket)
Autoclave cooling (touching container).
Blue bath solution.
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Highly purified water
Application of highly purified water:
Manufacturing of ophthalmic products.
 Manufacturing of sterile nose/ear preparations.
 Manufacturing of sterile preparations for
Cutaneous use.
 Final rinsing of equipment, containers and covers for
sterile parenterals, if a later depyrogenation step is
carried out.
Highly purified water is made from potable water, by
double-step reverse osmosis combined with other suitable
procedures such as ultrafiltration or deionization.
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Water for injection
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Application of water for injection in bulk:
Manufacturing of parenterals
(aseptic manufacturing)
Manufacturing of parenterals
(final sterilization)
Final rinsing of equipment, containers and caps
for category 1 products
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Sterilized Water for Injection
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Sterilized Water is produced by filling water for
injection into adequate containers which are
sealed and sterilized by heat.
Sterilized Water for Injection has to fulfill the
test for bacterial endotoxins and must not
contain any additives.
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Water for Injection: special USP
monographs
The USP also distinguishes between the following
types of water for injection, unlike the European
pharmacopoeia:
1.
2.
3.
4.
Bacteriostatic water for injection
Sterile water for inhalation
Sterile water for irrigation
Water for hemodialysis
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Generation of Purified Water
In order to produce the chemical &
microbiological quality water types and at the
same time comply with the regulations, certain
instruments are required for the generating
purified water.
The raw water must be:
 Pretreated before actual purification.
Thus, a facility for generating purified water
consists of several steps, which are described next:
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Air-break
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In order to protect the public water supply from
contamination, it is necessary to install an air-break
between the first processing step in the generation of
purified water and the feed of potable water.
This is in order to prevent reverse contamination in the
public water supply.
The systems can be separated in various ways.
1) Install a supply separation container.
2) Use a supply or non-return valve.
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Softener
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The potable water is first coarsely filtered, then the
scale (calcium, magnesium, sulfate, carbonate) is
removed in a first stage.
A choice procedure would be softening using ion
exchange technology.
A sodium exchanger can be used for this purpose.
The magnesium and calcium ions present in the water
are deposited in the resin in exchange for sodium ions.
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Exchanger
materials
Na+
Exchanger
materials
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Removal of chlorine
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Only potable water can be used to generate
pharmaceutical water.
However, the composition can vary greatly and it is
possible that the potable water may have been
chlorinated.
As the raw water must be free from oxidation media, dechlorination must be carried out through the use of
either:
1. Activated charcoal filters. or
2. Sodium bisulfite (Na2HSO3).
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Activated charcoal filter
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The use of an activated charcoal filter for dechlorination of the potable water is a simple & very
effective method.
Activated charcoal absorbs low molecular weight
organics, such as chlorine and chloramine
compounds.
However, when manufacturing ultra pure water the
use of activated charcoal could be problematic. The
risk of increased microbiological fouling and the
formation of a biofilm is very high.
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Dosage of sodium bisulfite
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Sodium bisulfite is added to the raw water.
Sodium bisulfite combines with the chlorine,
which is then separated through reverse
osmosis.
The added quantity must be adjusted.
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Removal of carbon dioxide (CO2)
Carbon dioxide represents a problem when
generating purified water via reverse osmosis, as it
is not retained by the reverse osmosis membrane
and thus leads to increased conductivity.
Two methods are used to remove carbon dioxide:
1. Dosage of sodium hydroxide solution: The carbon
dioxide is converted into carbonate, which is
retained by reverse osmosis.
2. Membrane degassing: Through the creation
pressure difference and are rinsed from the
membrane using air.
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Reverse osmosis
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Deionization and removal of microorganisms can be
carried out in the reverse osmosis unit.
Reverse osmosis is a physical operation which takes place
on membranes. It reverses the process of osmosis.
A semipermeable membrane retains cations, anions
colloidal systems and bacteria.
The membrane lets through water that is almost pure.
With reverse osmosis, more than 98 % of salts and 90 %
of organic compounds are retained, as well as bacteria and
organisms.
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
In order to reverse the process of osmosis,
pressure higher than the osmotic pressure
must be applied to the concentrate stream
in order to push water with a low amount
of solids through the membrane.
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Reverse osmosis mechanism
Reverse Osmosis
Reverse Osmosis
Remove particles, bacteria,
pyrogen, organic, inorganic
ions and silica
Reverse Osmosis
Electro-deionization (EDI, CDI)
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Electro-deionization (CDI = Continuous
Deionization; EDI = Electro-deionization.
EDI works by coupling the behavior of ions in
the electrical field with membrane technology.
The anions wander towards the anode.
The cations are transported towards the cathode
in the same manner.
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Advantages of EDI
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High purification level (>98%) with small membrane
area.
Continuous operation through self-regeneration.
No use of chemicals for regeneration or neutralization.
Retention of high pH values through water division and
thus regeneration
Optimum carbon dioxide, silicate and TOC removal
Prevention of multiplication of microorganisms.
Low energy consumption (0.1–1.0 KW/m3) with very
low voltage.
Minimum space requirement due to compact design of
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the module
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Ultra filtration
Ultra filtration (UF) is a separation technology
for separating particles with a size of 0.001 to
0.1 μm.
 For ultra pure water production UF hollow
fiber membranes are usually used.
 The conductivity of the permeate remains
nearly the same as that of the feed water.
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Ion exchanger
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In the ion exchanger (separate bed and mixed
bed system) ions are removed from the water.
Ion exchangers are filled with special resins
which are usually produced from synthetic
polymers as balls (particle size 0.3–1.5 mm.
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2. Ion-Exchange
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The ion-exchange equipment involves the
passage of water through a column of:
Cation and Anion exchangers.
Resin is:
Water-insoluble materials
synthetic, polymerized phenolic,
carboxylic, amino, or
sulfonated materials
high molecular weight.
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Types of Resins
1. The Cation or acid exchangers.
Which permit the exchange of Cations +
Na+, Ca++, Mg++, etc, (in solution in the tap
water) with hydrogen ion from the resin.
2. The Anion-, or base exchange resins.
which permit the removal of anions in solution
in the tap water with Cl
The process is as follows:
(M+) indicating the metal or Cation as (Na+)
(X-) indicating the Anion as (Cl-)
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Cation Exchange
H-Resin + M+ + X- + H2O  M-Resin + H+ + X- +
H2O.
Anion Exchange:
Resin-NH2 + H+ + X- + H2O Resin-NH2 . HX + H2O
Pure.
Purified water in this method is named as demineralized or
de-ionized water.
Used in any pharmaceutical preparation or prescription.
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Purification plants
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The particular combination of procedures usually
depends on the feed water quality. Usually, the
analysis results from the potable water supplier
can be used for initial planning regarding which
combinations will give the desired result.
There are feed water qualities for which the
combination of reverse osmosis with an EDI is
sufficient for the generation of purified water.
For other feed water qualities, softening, reverse
osmosis, CO2-degassing and EDI must be
combined to achieve the same result.
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Distilled Water / Distillers
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It’s an Instrument used to generate distilled
water, by boiling the water and collect the steam
in a clean container.
This water which called Distilled water used
mainly in the preparation of injectable products
such as IV. Solutions, Ampoules, Eye drops, and
Liquid Vials.
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Distilled Water

Distilled water is water that has virtually
all of its impurities removed through
distillation. Distillation involves boiling the
water and then condensing the steam into a
clean container, leaving most if not all solid
contaminants behind.
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Procedure combination for generation purified water
System1
Activated
charcoal filter
X
Softener
X
System 2
System 3
X
X
System 4
System 5
X
X
Mixed bed
technology
X
Ultra filtration
X
System 6
X
X
X
Reverse osmosis
X
Degassing
X
X
EDI/CDI
X
X
X
X
X
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Water System
Softening
Reverse
Osmosis
Softening
Waste Water
Waste Water
Reverse
Osmosis
Purified Water
Waste Water
Reverse
Osmosis
Electro
Deionization
Waste Water
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Water for injection (WFI)
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Water for injection (WFI) is required for the
production of sterile medicinal products.
The requirements of manufacturing procedures for
WFI are different in the USA, Japan and Europe (see
Figure 5.B-9).
Permissible manufacturing procedure for WFI
Europe
Distillation
USP
Distillation or other equivalent or superior
processes
Japan
Ultra filtration or distillation
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Pretreatment –
schematic drawing
float
operated
valve
excess water recycled
from deioniser
air filter
activated
carbon
filter
sand filter
To water
softener &
DI plant
spray ball
Water is kept
circulating
raw water in
break tank
air break to drain
centrifugal pump
« S” trap to sewer
cartridge
filter
5 micrometers
Typical de-ionizer
from water softener
Water
must be
UV light
kept
circulating
HCl
NaOH
6
6
5
4
3
2
1
5
4
3
2
1
Cationic column
Anionic column
Cartridge
filter 5 µm
Eluates to
neutralization
plant
Cartridge
filter 1 µm
Ozone generator
Hygienic pump
Return to de-ioniser
Outlets or storage.
Drain line
Air break to sewer
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Typical 2-Stage RO Schematic
Water from softener or de-ioniser
Second stage reject water goes back to first stage buffer tank
1st stage reject concentrate
1st stage buffer tank
First stage RO cartridge
Branch
Branch
First stage filtrate feeds second stage RO
with
. excess back to 1st stage buffer tank
Air break
to sewer
2nd stage buffer tank
Second stage RO cartridge
High pressure
pump
Second stage RO water
meets Pharmacopoeia
standards
Cartridge
filter 1 µm
Hygienic pump
Water returns to 1st stage buffer tank
Outlets or storage
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Purified Water USP 23
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Purified Water is described in the USP 23
monograph as follows:
"Purified Water is water obtained by distillation, ionexchange 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 USP

Purified water is obtained by:
1. Distillation.
2. Ion-Exchange.
3. Reverse osmosis.
4. Other suitable method.
It is prepared from the drinking water.
It is more free of solid impurities.
When evaporated to dryness, it must not yield
greater than 0.001% of residue (1mg of total solids
per 100 ml of sample evaporated).
Thus it is 100 times more free of solids than the
drinking water.
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Water system design (1)
There should be no dead legs
D
Flow direction arrows
on pipes are important
Deadleg section
X
If D=25mm & distance X is
greater than 50mm, we have
a dead leg that is too long.
<2D
Sanitary Valve
Water scours deadleg
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Water system design
1. Pipes sloped so water does not pool and
can drain easily
2. Sanitary fittings & connections
3. Constructed of suitable materials such as
stainless steel
4. Circulate the water
5. Incorporate non-return valves (NRV)
Sampling
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There must be a sampling procedure.
Sample integrity must be assured.
Sampler training
Sample point
Sample size
Sample container
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