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Supplementary Training Modules on

Good Manufacturing Practice

Water for
Pharmaceutical Use
Part 2:
Water purification and
engineering
WHO Technical Report Series
No 929, 2005. Annex 3

Water

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January 2006

Water for Pharmaceutical Use


Objectives
To examine the basic technology and requirements for:
Water treatment systems
Storage and distribution requirements
Sampling and testing
Sanitization
6.

Water

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Water for Pharmaceutical Use


General
Part 1 reviewed types of water and water purification
systems
Water can be used directly, or stored in a storage vessel for
subsequent distribution to points of use
Design appropriately to prevent recontamination after
treatment
Combination of on-line and off-line monitoring to ensure
compliance with water specification
6.1

Water

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Water for Pharmaceutical Use


WPU system contact materials
Contact materials include:

Pipes
Valves and fittings
Seals
Diaphragms and instruments
Tanks
Pumps, etc.

Proper selection to ensure these are suitable


6.2

Water

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Water for Pharmaceutical Use


WPU system contact materials (2)
Factors to consider (including components)
Compatibility and leaching effect
Corrosion resistance
Smooth internal finishing, ease of jointing
Hygienic / sanitary design
Documentation
Materials of construction (MOC) - (including original/certified
copies of material certificates
6.2

Water

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Water for Pharmaceutical Use


WPU system contact materials (3)
Compatibility
With temperature and chemicals used in the system
Leaching effect
Non-leaching at temperature range
Corrosion resistance
PW, HPW, WFI highly corrosive
Stainless steel Grade 316L to be used
System passivated after installation and modification
according to SOP
Water

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6.2

Water for Pharmaceutical Use


WPU system contact materials (4)
Smooth internal finish
Biofilms and microbial contamination
Crevices and roughness result in problem areas associated
with contamination and corrosion
Internal finish to have arithmetical average surface
roughness not greater than 0.8 micrometer arithmetical
mean roughness (Ra)
Mechanical and electropolishing needed when stainless steel
is used
6.2

Water

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Water for Pharmaceutical Use


WPU system contact materials (5)
Joints
System materials easily jointed, e.g. by welding
Process controlled including requirements such as:
Qualification of operator
documentation of welder set up
work session test pieces
weld logs
visual inspection of defined proportions of welds
6.2

Water

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Water for Pharmaceutical Use


WPU system contact materials (6)
Suitable materials include:
Stainless steel Grade 315 L (low carbon)
Polypropylene (PP)
Polyvinylidenedifluoride (PVDF)
Perfluoroalkoxy (PFA)

Unplasticized polyvinylchloride (uPVC) used for nonhygienic designed water treatment equipment such as ion
exchangers and softeners
6.2

Water

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Water for Pharmaceutical Use


System sanitization and bioburden control
Systems in place to control proliferation of microbes
Techniques for sanitizing or sterilization
Consideration already during design stage then validated
Special precautions if water not kept in the range of 70 to 80
degrees Celsius
6.3

Water

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Water for Pharmaceutical Use


Storage and distribution - Storage vessels
Design and size important
Serves as buffer between generation and use
Avoid inefficiencies and equipment stress during frequent onoff cycles
Short-term reserve in case of failure
Contamination control consideration
Headspace (kept wet with spray ball / distributor device)
Nozzles (no dead zone design)
6.4
Vent filters (type, testing, use of heat)
Pressure relief valves and burst discs (sanitary design)
Water

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Water for Pharmaceutical Use


Storage and distribution Pipes and heat
exchangers
Continuous circulating loop needed
Filtration not recommended in loop and take-off point
Heat exchangers:
Double tube plate or double plate and frame type
Designed to ensure no stasis of water
Where water is cooled before use, done in minimum time, and
validated process
6.5, 6.5.1
Water

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Water for Pharmaceutical Use


Storage and distribution Circulation pumps
Sanitary design with appropriate seals
Standby pumps
Can be used
Configured or managed in a way to avoid trapped dead
zones

6.5.2
Water

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Water for Pharmaceutical Use


Typical water storage and distribution schematic
Hydrophobic air filter
& burst disc

Feed Water
from
DI or RO

Cartridge
filter 1 m

Water must
be kept
circulating

Spray ball

Optional
in-line filter
0,2 m
UV light
Outlets

Heat Exchanger
Ozone Generator
Water

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January 2006

Hygienic pump

Air break
to drain

Water for Pharmaceutical Use


Biocontamination control techniques
Continuous turbulent flow circulation
Specified velocity proven (qualification), and monitored
Avoid dead legs
Hygienic pattern diaphragm valves
Shortest possible length of pipe work
Pipe work of ambient temperature systems, isolated from hot
pipes
6.5.3

Water

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Water for Pharmaceutical Use


Biocontamination control techniques (2)
There should be no dead legs
D
Flow direction arrows
on pipes are important
Dead leg section

If D=25mm & distance X is


greater than 50mm, we have
a dead leg that is too long

>1.5D

Sanitary Valve
Water scours dead leg
Water

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Water for Pharmaceutical Use


Biocontamination control techniques (3)
1. Ball valves are unacceptable
2. Bacteria can grow when
the valve is closed
3. The water is contaminated as it
passes through the valve

Stagnant water
inside valve

Water

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Water for Pharmaceutical Use


Biocontamination control techniques (4)
Pressure gauges separated from system membranes
Pipe work laid to fall (slope) allows drainage
Maintain system at high temperature (above 70 degrees Celsius)
Use UV radiation
Flow rate, life-cycle of the lamp
Suitable construction material
6.5.3

Water

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Water for Pharmaceutical Use


Biocontamination control techniques (5)
Periodic sanitization with hot water
Periodic sanitization with super-heated hot water or clean steam
Reliable
Monitoring temperature during cycle
Routine chemical sanitization using, e.g. ozone
Removal of agent before use of water important
6.5.3

Water

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January 2006