Water systems

www.alfalaval.com© Alfa Laval Slide 1
• The most common and well known system in the
pharmaceutical industry.
• Still, many confusions on how to select the most
suitable, hygienic and cost effective solution
• The key is to understand the basic principle
Water Systems

Feed
water
Reverse
osmosis
Electro-
deionisation Tank
Distillation system
Tank
Purification process
Distribution loop
Purification & Distribution Loop

Purification process
• Dechlorination
• Carbon Filtration
• Injection of Reducing Agents
• UV Light
• Ion Removal
• Membrane Processes (RO, Nanofiltration)
• Ion Exchange
• Distillation
Selection of purification steps depends on water source quality and
output water demands

ISPE differentiate between three types of water
• USP Purified Water (PW)
• USP Water for Injection (WFI)
• Non-compendial water (RO, DI, etc.)
Definitions
ISPE International Society for Pharmaceutical Engineering
USP US Pharmacopeia

All Pharmaceutical water must also meet the EPA standard for microbiological quality
of potable water
PW (Purified Water) WFI (Water for Injection)
Water conductivity and
pH
(< 1.3 S/cm @ 25°C)
pH 5-7
(< 1.3 S/cm @ 25°C)
pH 5-7
Total Organic Carbon
(TOC)
< 0.5 ppm < 0.5 ppm
Aerobic Microbial
Contamination
< 100 CFU/ml < 0.1 CFU/ml
(10 CFU/100 ml)
Endotoxin content Not Specified < 0.25 EU/ml
Production
Methods
Obtained by suitable
process
Obtained by suitable
process and purified by
Distillation
USP Specifications

WFI & PW, in practice
Sterile bulk
API or BPC
Bulk API or
BPC
Non-
parenteral
dosage form
Parenteral
dosage form
WFI PW
Suitable non-
compendial
API = Active Pharmaceutical Ingredient
BPC = Bulk Pharmaceutical Chemical
Parenteral = Not by mouth (i.e. injectable)
Water usage
Minimum
water type
Equipment cleaning and rinsing
ISPE recommendation

Bacteria basics for water systems
Most common bacteria in pharmaceutical water systems are Gram
negative bacteria. Gram negative bacteria do not grow above 60ºC,
however, cautions for Gram positive bacteria, which are more heat
resistant, should be taken and periodic sanitization and test procedures
are recommended.
Bacteria in pharmaceutical water systems generally range from 0,3 m
– 5 m.

Killed Gram negative bacteria releases endotoxins, which is a
lipopolysaccharide molecule that cause fever when injected into the
bloodstream. (These substances are termed ”pyrogens” meaning
generating heat, fever). Pyrogens have also been linked to more serious
reactions when injected into the blood (e.g. lethal septic shock) and are a
major concern for every dosage form in contact with the blood stream.
Endotoxins are heat stable (boiling for 30 minutes does not destabilize
endotoxin), but certain powerful oxidizing agents such as superoxide,
peroxide and hypochlorite, degrade them.
Endotoxins are commonly removed by RO, UF, (UV*) and flushing
* Argued by some UV manufacturer

Development of biofilm in water pipes and tanks is another
common 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 physical conditions such as
O2 concentration, temperature, and pH.

Bacteria structure
Profiles of the cell envelope the Gram-positive and Gram-negative bacteria. The
Gram-positive wall is a uniformly thick layer external to the plasma membrane. It is
composed mainly of peptidoglycan (murein). The Gram-negative wall appears thin
and multilayered. It consists of a relatively thin peptidoglycan sheet between the
plasma membrane and a phospholipid-lipopolysaccharide outer membrane. The
space between the inner (plasma) and outer membranes (wherein the
peptidoglycan resides) is called the periplasm.

Bacteria and Temperature
Growth rate vs temperature for five environmental classes of
procaryotes. Most procaryotes will grow over a temperature range of
about 30 degrees.

Microbial Growth
• Microbial growth mainly
occur between 10-55ºC.
• Conditions above 65-75ºC
are considered self-sanitized
• Conditions below 10ºC are
considered to limit bacterial
growth
*ANNE M. BRONIKOWSKI, ALBERT F. BENNETT, AND RICHARD E. LENSKI, Evolution, 55(1), 2001, pp. 33–40
Typical temperature/growth curve for bacteria

Bacteria and pH
Growth rate vs. pH for three environmental classes of
procaryotes. Most free-living bacteria grow over a pH range
of about three units.

Bacteria and Water Concentration
Growth rate vs water activity (Aw), a measure of the concentration of water (H2O) in a
solution (pure H2O has Aw 1,0).From left to right the graph shows the growth rate of a
normal (nonhalophile) such as E. coli or Pseudomonas, the growth rate of a halotolerant
bacterium such as Staphylococcus aureus,and the growth rate of an extreme halophile
such as the archaean Halococcus.

USP Specifications in Practice
Purified water used for non-injectable drugs can accept a small amount
of microbial contamination and has no specifications on endotoxin.
WFI used for injectable drugs are expected to be free from
microorganisms but since some microorganisms may be encountered
during sampling, an action limit of 10 CFU/100 ml is commonly specified.
In WFI endotoxin are a concern and if bacteria are introduced to the
system and killed, these bacteria will release endotoxin. Therefore, strict
measurement has to be taken not to introduce any bacteria into the
system and to secure that the small amount of bacteria in the system
has no possibility to grow.

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• Maintain the water quality within acceptable limits
• Deliver the water to the points-of-use at required flow &
temperature
• Minimize capital & operating expense
Goals for Water Systems

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• Minimizes the time water is held at conditions which favor
growth
• Minimizes amount of water which changes temperature
• Minimize the exposure of the water to the environment
(closed system)
• Contact all surfaces during sanitization
Optimum System

Sanitization
• Typically with hot water at 75-85ºC
• Temperatures above 85ºC will increase the risk for
rouging, cavitations or boiling in circulation pump
• Flushing of the whole system, including sampling
points and point of use, until required water quality
achieved (typically 2 to 3 hours)
• Other types of sanitization can be steam or ozone

Storage and distribution
ISPE present 8 common distribution configurations*
* ISPE Baseline Guides– Volume 4: Water and Steam Systems – January 2001
These can be divided in 3 different temperature types:
• Hot water systems (self sanitised)
• Ambient water systems (needs sanitization)
• Cold water systems (needs sanitization)
Examples

Questions to be raised
• Quality of water from purification process?
• Capacity of purification process?
• Water usage and frequency?
• Temperature of water?
• Quality of water?
• Possibility for sanitization cycles

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T
Steam
Cond.
Hot
Storage
Tank
Control Valve
(optional)
Hot Storage, Hot Distribution
Most used when
• Hot water is required
• Hot water is generated
• Microbial control is critical
Least used when
• Ambient temperature water
required

Coolant
Point of Use
T
Hot Loop Hot Loop
Sanitization is accomplished using low pyrogen steam
or flushing before use.
Point of Use, Steamed

Sanitization is accomplished by circulating hot water from the loop,
through the point of use exchanger to the main loop.
Coolant
Point of Use
T
Hot Loop Hot Loop
Restriction Orifice
Point of Use Installed in Subloop

Coolant
Point of Use
Hot Loop Hot Loop
Sanitization in this example is accomplished by flushing hot water
from the main loop once through to drain.
Point of Use Heat Exchanger
with Multiple, Branched Users

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Steam
Hot
Storage
Tank
Cooling Heat
Exchanger
Coolant
Coolant
T
Cond.
Reheat Exchanger T
Cond.
SteamControl Valve
(optional)
Hot Storage, Cool & Reheat
Most used when
• Hot water is generated
• Tight microbial control is required
• There is little time for sanitization
• Water consumption is critical (no flushing)
Least used when
• Energy consumption is critical

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Steam
Hot
Storage
Tank
Cooling Heat
Exchanger
Coolant
Coolant
T
Cond.
Reheat Exchanger
T
Cond.
Steam
Control Valves
(optional)
Most used when
• Multiple temperatures are required
• A single loop becomes cost prohibitive
• Hydraulic limiting
Least used when
• Loop balancing is critical
Parallel Loops, Single Tank

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Control Valve
Coolant
Coolant
Cold
Storage
Tank
Sanitizing /Cooling
Heat Exchanger
T
Cond.
Steam
(optional)
Coolant
Coolant
Most used when
• High peak demands for ambient or cold water
• Water is generated at ambient temperature
• There is adequate time for sanitization
Least used when
• Sanitization will not fit into
operating schedule
Cold Storage, Cold Distribution

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Steam
Hot
Storage
Tank
Cooling Heat
Exchanger
Coolant
Coolant
T
Cond.
Control Valve
(3-way)
(80% of flow)
(20% of
flow)
Most used when
• Water is generated hot
• There are many low temperature water users
• Energy consumption is critical
Least used when
• Per unit energy cost is a concern
• Tank turnover is a concern
Hot Storage, Self-Contained
Distribution

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Control Valve
(optional)
Most used when
• Non-reliable generation method
• QA release required before water use
Least used when
• Capital and operating cost are a
concern
Batch Tank Recirc System

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Coolant
Coolant
Storage
Tank
Control Valve
(optional)
UV Light
(Ozone
Destruct)
Ozone
Generator
v v v v v v v
Sparge Bar
AIT
Ozone
Most used when
• Production allows periodic automatic sanitization
• Energy costs are high
• All users are ambient
Least used when
• Capital cost is tight
• Product is ozone sensitive
Ozonated Storage & Distribution

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T
Points Of Use
Restriction Orifice
(mount in vertical)
Steam
T
Cond.
Most used when
• Capital is tight
• Microbial control is not critical or not required
• Water use is continuous
• Frequent flushing or sanitization
Least used when
• Water use is sporadic, because
line stays stagnant
• Operating cost is a concern
Branched/One Way

Validation strategy
A. Design/installation review:
A complete and up-to-date description and design
drawing of the system included in the final report
(including all components and clearly identify all
sample points and their designation) to ensure that
the validation is not put at risk and is successfully
completed

Validation strategy
B. SOP development and confirmation
Develop the operational parameters and cleaning
and sanitising protocols. Collect data over a period
of two to four weeks, samples collected daily after
each purification step and from all point of use. If
successful, these procedures are established as
the water system's SOPs

Validation strategy
C. Demonstration of effectiveness
Demonstrate that the water system consistently
produces water of the desired quality when operated
within the parameters outlined in the SOPs over a
long period of time. WFI system samples are taken
daily at a minimum from one point of use and weekly
from all point of use. This identifies any
inconsistence in the feed water quality due to
seasonal variations. The water system can be
considered validated after the manufacturer has a
year’s worth of operational data.

Validation strategy
D. Data compilation and sign-off
Assembly the data into a validation report including
all the data collected in steps B and C. Once
completed, ensure that the appropriate personnel
review and sign off are done.

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• Select the design based on “return on investment,
where “return” is defined as the reduction in
contamination risk
• Utilize design features that provide the greatest
reduction in contamination risk at the most
reasonable cost
• Add the more expensive features only if they are
required to maintain quality within the acceptable
limits
The Key Points

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Total Cost (= Investment + Operating)
Time
Investment
cost
Typical Dilemma

5 Ideas To Reduce Cost
1. Ra < 0.8 µm enough for hot systems
2. For most loops use one distribution pump with
warehouse spare
3. Use manufacturer’s standard equipment where
possible
4. Use Plate Heat Exchanger with circulation where
possible
5. Single mechanical seals on pumps

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Automatic Welds Cheaper than hand welds
316L SS Same cost as 304 SS
Mechanical Polish Electropolish very expensive
Velocities 2 to 3 M/sec at pump outlet,
0.6 to 1 M/sec min return
Vent Filters Required, avoid condensation
Positive Pressure Required
What Makes Sense?

Water systems

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