Water (2012)

WATER SYSTEM
2012
DESIGN PHILOSOPHIES
• Pharmaceutical water is the most widely used ingredient
in drug manufacturing and the main component in
equipment/system cleaning.
• Control of chemical and microbiological quality is
important
• It must be demonstrate that all pharmaceutical water can
be produced consistently to specification
DESIGN PHILOSOPHIES
♦ Specification of pharmaceutical water quality:

Pharm.water uses can be categorized as :
a. Ingredients in a dosage form manufacturing process,
b. Ingredient in an API process,
c. Equipment cleaning or rinsing
♦ Critical process parameter :
Parameters, which directly affect the water quality at ,or after, a
treatment step
DESIGN PHILOSOPHIES
♦ cGMP compliance issues,f.i :

a. Continuous,turbulent flow
b. Elevated or reduced temperature
c. Smooth,clean surfaces
d. Flood distribution loop
e. etc
DESIGN PHILOSOPHIES
♦ Design Range vs Operating Range
Types of water used in
pharmaceutical processes
• Purified water
• Water for Injection
• Water for hemodialysis
• Pure, or clean steam
USP Purified Water
• Is obtained from water complying with U.S.
- Environmental Protection Agency (EPA),
- National Primary Drinking Water Regulations (NPDWR),
- or comparable regulations of the European Union or Japan,
- and will be referred to subsequently as Drinking water.
• Contain no added substance
• Is obtained by a suitable process
• Meets the requirements for water Conductivity
• Meets the requirements for TOC
USP Water For Injection
• Meets all of the requirements for “Purified water”
• Is water purified by distillation or a purification process
that is equivalent or superior to distillation in the removal
of chemicals and microorganism
• Meets the requirements of the Bacterial Endotoxin test
and contains not more than 0.25 EU/mL
• Is prepared using suitable means to minimize microbial
growth.
USP Specifications: PW vs. WFI
PW (Purified WFI (Water for
Water) Injection)
Water conductivity < 1,3 μS/cm at < 1,3 μS/cm at 25°C*
and pH 25°C* pH 5-7 pH 5-7
Total Organic Carbon < 0.5 ppm < 0.5 ppm
(TOC)
Aerobic Microbial < 100 CFU/ mL < 10 CFU/100 mL
Contamination (<0.1 CFU/mL)
Endotoxin content Not Specified < 0.25 EU/mL
Production Obtained by Obtained by suitable
Methods suitable process process and purified by
distillation.
*In-line measurement, from equivalent values from USP table

CFU=Colony Forming Units
All Pharmaceutical water must also meet the EPA standard for microbiological
quality of potable water
Why Purify Raw Water?
• Although reasonably pure, it is always variable
• Seasonal variations may occur in water
• Some regions have very poor quality of water
• Must remove impurities to prevent product contamination
• Control microbes to avoid contaminating products
Major Water Impurities
•Non Ionic & Suspended

•Gases Purification
techniques
•Ionic & Dissolved
Non Ionic & Suspended
• Silt, Mud, Dirt
• Organic Matters
• Oil, Bacteria
• Colloidal silica
Should be removed or greatly reduced

by pre treatment
Gases
• Carbon dioxide
• Oxygen
• Ammonia
• Methane
• Chlorine
• Hydrogen Sulfide
Ionic & Dissolved
• Inorganic Ions
• Charged Organic Material
• Soluble Silica
Biofilm
A biofilm is defined as bacterial cells adherent to each
other and/or to surfaces or interfaces and are covered
by a slimy substance, which acts as a shield, protecting
the biofilm from physical and chemical attack.
Ref: Biofilms – Survival and growth of bacteria in compendial high purity water systems by Frank Riedewald and Aidan W. Sexton:
Pharmaceutical engineering Vol.27 No 1.
Bio-film formation
1. Free swimming aquatic bacteria use
polymucosaccharides to colonise surfaces
2. Complex communities evolve which shed
micro-colonies and bacteria
SOURCE OF RAW WATER
1. Rain water
2. Surface or ground water
3. Well or borehole
4. Municipal or civil – “tap water”
5. Purchased in bulk
Treatment Guidance
• The following should be monitored :
– Sources of water
– Treatment Procedures
– Water Treatment Equipment
– Treated water tests
– Monitoring records required
Selection of Water for Pharmaceutical Purposes (USP)
WATER FOR PHARMACEUTICAL PURPOSES (USP)
Materials that come into contact with
systems for WPU
• Includes : Pipe work, valves and fittings, seals,
diaphragms and instruments, should be selected
to satisfy the following objectives.
► Compatibility : All materials used should be
compatible with the temperature and chemicals used by
or in the system.
► Prevention of leaching: All materials should be non-
leaching at the range of working temperatures.
► Corrosion resistance : PW, HPW and WFI are
highly corrosive. All materials should be corrosion
resistance.
systems for WPU
► Smooth internal finish :Smooth internal surfaces

help to avoid roughness and crevices within the WPU
system. Crevices are frequently sites where corrosion
can commence.
► Jointing : The selected system materials should be
able to be easily by welding in a controlled manner.
► Design of flanges or unions : Where flanges or
unions are used, they should be of a hygienic or sanitary
design
systems for WPU
► Documentation : All system components should be

fully documented and be supported by original or
certified copies of material certificates.
► Materials : Suitable materials that may be
considered for sanitary elements of the system include
316 L (low carbon) stainless steel, polypropylene,
polyvinylidenedifluoride and perfluoroalkoxy
(WHO, Technical Report Series 929/2005)
SYSTEM DESIGN
• Type of products to be manufactured
• Pipes sloped so water does not pool and can be
drain easily
• Sanitary fittings & Connections
• Constructed of suitable materials
• Temperature of the systems
• Circulating or one way system ( a one way
systems is basically “dead leg”)
• Level of Quality that is desired
SYSTEM DESIGN
• Incorporate non return valves
• Purified water systems require frequent
sanitization and microbiological monitoring
to ensure water of appropriate
microbiological quality at the point of use.
PIPE SYSTEM DESIGN
Flow direction arrows

on pipes are important
Deadleg section
X <2D
If D=25mm & distance X is
greater than 50mm, we have
a dead leg that is too long.
Sanitary Valve
Water scours deadleg
There should be no dead legs

Water purification & distribution loop
Purification process
Distillation system
Reverse Electro-
Feed osmosis deionisation Tank
water
Tank
Distribution loop
Hot Storage, Hot Distribution
Control Valve
(optional)
Steam
Hot
Storage
Tank
Cond.
Most Advantageous When: Least Advantageous When:
•Hot water is required •Ambient temperature water
•Hot water is generated required
•Microbial control is critical
Hot Storage, Cool & Reheat
Control Valve Steam
(optional)
T
Reheat Exchanger
Cond.
Steam
Hot
Storage Coolant
Tank
T
Cooling Heat
Exchanger
Cond. Coolant
Most Advantageous When:

•Water is generated hot
•Tight microbial control is required
•There is little time for sanitization Least Advantageous When:
•Water consumption is critical (no flushing) •Energy consumption is critical
How to validate a water treatment system (USP)
• Defines the critical process parameters and their
operating ranges.
• A validation programs the design, installation, operation
and performance of equipment.
• Stages :
- Qualification of the installation (IQ),
- Operational Qualification (OQ),
- Performance Qualification (PQ)
• Validation
Validation of Water System
• Consists of three phases :

• Phase 1 : 2-4 weeks
• Phase 2 : 4 weeks
• Phase 3 : 1 year
Phase 1: Investational Phase (2 – 4 weeks)
• DQ, IQ and OQ
• Develop
– operational parameters
– cleaning and sanitization procedures and
frequencies
• Sample daily at each point of use
• End of Phase I, develop SOPs for the water
system
Phase 2 : verifying control (4 - 5 weeks)
• Demonstrate the system is in control

• Same sampling as in phase 1
Phase 3 : verifying long-term control (1 year)
• PQ
• Demonstrate the system in control over a long
period of time
• Weekly sampling
References
1. USP 32-NF 29 (2009).
2. WHO-TRS 929,39th Report (2005)
3. ISPE Baseline Guide,Vol.4 : Water and Steam System,
1st ed.(2001)

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WATER SYSTEM

♦ Specification of pharmaceutical water quality:

♦ cGMP compliance issues,f.i :

*In-line measurement, from equivalent values from USP table

•Non Ionic & Suspended

Should be removed or greatly reduced

► Smooth internal ﬁnish :Smooth internal surfaces

► Documentation : All system components should be

Flow direction arrows

There should be no dead legs

Most Advantageous When:

• Consists of three phases :

• Demonstrate the system is in control

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