PW and WFI

STORAGE and DISTRIBUTION

SYSTEMS
DESIGN and OPERATION
A PRACTICAL COMPARISON
Scope and Purpose
 Discussion on the Basis of Design of PW and WFI systems
 Requirements:
 Uses of water
 Quality
 Design
 Construction
 Critical parameters
 Sampling

March 1-2, 2017 PW AND WFI DESIGN AND OPERATION 2

Disclaimer
 All information is widely available:
 On Internet
 Regulatory publications
 Standards
 Guides
 Professional publications
 Other sources
 There is “regulation” “interpretation” “current practice” “best practice”
 There is no one way of doing things
 Everyone has to decide for himself
 This presentation is about GMP related engineering aspects

March 1-2, 2017 PW AND WFI DESIGN AND OPERATION 3

Clarification
The following are not in the scope of this discussion:
User Requirement Specification (URS) and a Functional Design Specification (FDS)
Detailed specifications for the equipment design, construction and
Detailed specifications for pipeline installation, slope measurement, cleaning and
passivation
Detailed engineering design, commissioning and operation of the critical system
Inspection and Verification / Qualification / Validation requirements

March 1-2, 2017 PW AND WFI DESIGN AND OPERATION 4

Definition
 The storage and distribution system has the role to provide a buffer by
holding the required quantity of water, based on the daily water usage and
the water generation capacity, and supply it to the users at the points of use
(POU), while maintaining the chemical and microbial quality of water,
according to the specifications, defined in the company’s relevant SOPs.

 It is relatively easy to maintain the chemical quality of the water

 Maintaining the microbial quality is more of a challenge

March 1-2, 2017 PW AND WFI DESIGN AND OPERATION 5

March 1-2, 2017 PW AND WFI DESIGN AND OPERATION 6
 Applicable standards
◦ US Food and Drug Administration (FDA)
◦ 21 CFR Part 210
◦ 21 CFR Part 211
◦ 21 CFR Part 11
◦ Pharmacopeias of US, Europe, Japan (USP, EP, JP)
◦ Various GMPs from European countries
◦ EudraLex Volume 4, GMP Guidelines Part 1, Basic Requirements for Medicinal products
◦ Annex 1 Manufacture of Sterile products
◦ Annex 5 Manufacture of Immunological Veterinary Medicinal Products
◦ Annex 9 Manufacture of Liquids, Creams and Ointments
◦ Annex 10 Manufacture of Pressurized Metered Dose Aerosol Preparations for Inhalation
◦ Annex 11 Computerized Systems
◦ Annex 15 Qualification and Validation
◦ Other source of guidance:
◦ International Society of Pharmaceutical Engineers (ISPE), Baseline Guides
◦ American Society of Mechanical Engineers (ASME) Bioprocessing Equipment (BPE-2012)

March 1-2, 2017 PW AND WFI DESIGN AND OPERATION 7

Use of Water
Uses PW WFI
Feed water √ -
Washing √ √
Final rinse √ √
Formulation √ √
Humidification √ Pure Steam
Others (e.g. USP 1231)

March 1-2, 2017 PW AND WFI DESIGN AND OPERATION 8

Quality requirements
PW WFI
USP EU USP EU

Conductivity ≤ 1.3 µS/cm @25°C ≤ 4.3 µS/cm @20°C ≤ 1.3 µS/cm @25°C ≤ 1.1 µS/cm @20°C

TOC < 500 ppb < 500 ppb < 500 ppb < 500 ppb

Nitrate NO3 - ≤ 0.2 ppm - ≤ 0.2 ppm

Bacteria ≤ 100 CFU/ml ≤ 100 CFU/ml ≤ 10 CFU/100 ml ≤ 10 CFU/100 ml

Endotoxin - - ≤ 0.25 EU/ml ≤ 0.25 I.U./ml

pH 5-7

March 1-2, 2017 PW AND WFI DESIGN AND OPERATION 9

System boundaries
To be in control one must define where does the system start and where does it
end
Divide et impera

 The scope of the System starts at the generation system inlet / fill valve to
the Storage Tank
 The scope of the System starts at the inlet valve of any required utility
service, such as Pure Steam, plant steam, cooling water or compressed air
 The scope of the System terminates at the distribution system outlet valve of
any manual use point. Hoses used in the manufacturing process are
considered the responsibility of the production department
 The scope of the System terminates at the inlet valve of any directly
connected equipment, and includes any piping and components between
the loop outlet valve and the equipment inlet valve

March 1-2, 2017 PW AND WFI DESIGN AND OPERATION 10

Materials of construction
 All wetted parts should be type 316L stainless steel
 Type 316 stainless steel may be used if the component is fully annealed and is
not to be welded in the field
 The first component welded to the outside of any equipment should be of the
same material as the wetted component.
 Seals are EPDM, Viton, Teflon
 Thermal insulation should be of low chloride material

March 1-2, 2017 PW AND WFI DESIGN AND OPERATION 11

Surface finish
 The surface finish for all equipment and components in contact with the water
should be mechanically polished (PW) and then electropolished (WFI)
 There is a trend towards smoother and smoother surfaces and there are
questions as to what is too much
 ASME-BPE suggests 25 µinch (0.65 µm) and this may be sufficient
 It is important that the surface be electropolished for inspection purposes

March 1-2, 2017 PW AND WFI DESIGN AND OPERATION 12

Storage tank
 Proper sizing
 Rupture disk
 Double jacket

March 1-2, 2017 PW AND WFI DESIGN AND OPERATION 13

Vent filter
 The vent filter is prevented from getting wet by heating to a temperature
above the storage tank content, either electrically or by low pressure steam in
the filter housing jacket
 Filters should be equipped with an independent temperature monitor with
high and low temperature alarms
 For WFI the vent filter is integrity tested and steam sanitized
 For PW is a question of interpretation and decision
 The vent filter cartridge is of the membrane type, 0.2 μ absolute pore size, of
the hydrophobic type, suitable for pharmaceutical applications
 The vent filter housing is installed with sanitary clamp type fittings, to permit
easy removal of the housing

March 1-2, 2017 PW AND WFI DESIGN AND OPERATION 14

Pump
 All pumps should utilize the water being pumped, as a seal lubricant
 This may be by using a single mechanical seal or by using a double mechanical
seal with the pumped liquid being supplied to the seal chamber
 Redundancy (dual pumps)

March 1-2, 2017 PW AND WFI DESIGN AND OPERATION 15

Heat exchangers
 Shell and tube type heat exchangers should be of the double tube-sheet
design
 Heat transfer tubing should be full finish seamless construction
 Heat exchangers should be designed to be self-venting and self-draining on
both the tube and shell sides
 All liquid heating / cooling media or product should enter the bottom of the
heat exchanger and exit at the top
 Heating steam should enter the top of the heat exchanger and condensate
should be removed from the bottom
 The integrity of heat exchangers should be periodically verified by pressure
tested using a suitable test media

March 1-2, 2017 PW AND WFI DESIGN AND OPERATION 16

Piping
 Pipes are of sanitary tube type
 All piping shall be sloped to drain
 Pipelines are to be suitably identified as to contents and direction of flow
 No pipelines are permitted above open containers containing liquids that are
subject to microbial or chemical purity requirements
 Pipeline connections should be sanitary clamp type connections or welded

March 1-2, 2017 PW AND WFI DESIGN AND OPERATION 17

Valves
 Valves in water contact are to be of the sanitary diaphragm seal type
 Valve design should ensure that any leak is detected and does not permit
liquid to accumulate above the diaphragm
 Use of “zero dead leg” valves

March 1-2, 2017 PW AND WFI DESIGN AND OPERATION 18

Dead legs
 Dead legs are not allowed
 In the past the FDA has recommended that no dead-leg be longer than 6 times
the diameter of the branch line. The source of this value is unknown, but
believed to be from a different industry such as paint, for mixing of paint
colors or possible for line cleaning
 Some practices suggest reducing this to 3 or 4 diameters or as low as 2
diameters, however the aim should be to minimize the concern by use of
components that have minimum dead-leg, such as zero dead-leg valves and
short outlet tees.
 This is especially true for water systems operating at ambient temperatures.

March 1-2, 2017 PW AND WFI DESIGN AND OPERATION 19

Drainability and Slopes
 All parts of the equipment and piping are to be fully drainable
 Especially in WFI and PS systems
 Components that could have limited drainability, such as orifice discs, check
valves and small diameter valves and piping should be confirmed as being
properly installed or operated in a manner to ensure complete drainage.
 In systems that are not intended for steaming (PW systems), some dismantling
may be acceptable for full drainage.
 All pipelines must be sloped to drain

March 1-2, 2017 PW AND WFI DESIGN AND OPERATION 20

Backflow prevention
 Air-gaps are to be provided at all drain lines. Suitable air gaps are two times
the diameter of the drain pipe or 50mm, whichever is greater
 Air gaps are to be measured above the “flood level rim”, such as the top of any
area enclosed by a curb
 Air-gaps are required before the drain connection to any other liquid system
 At all locations where there is cross-connection with other systems there shall
be suitable means of backflow prevention
 At all water inlet connections to storage tanks dip pipes should not be used
and the upper liquid level should be below the bottom of any spray ball

March 1-2, 2017 PW AND WFI DESIGN AND OPERATION 21

Welds and weld inspection
 All pipeline welding should be of the automatic autogenous type gas tungsten
arc welding in accordance with the applicable Welding /Inspection Procedures
 Weld inspection should be 100% visual inspection by borescope and video
documenting

March 1-2, 2017 PW AND WFI DESIGN AND OPERATION 22

Cleaning and passivation
 After construction, changes to the system, and routinely the system is cleaned
and passivated according to the relevant SOP
 The system must have suitable vent and drain connections to permit field
cleaning and passivation

March 1-2, 2017 PW AND WFI DESIGN AND OPERATION 23

Operating parameters that are subject to
interpretation
 Some of the parameter values that were adopted many years ago have
become accepted practice, and while they may be desirable they may not
have a scientific basis for the accepted value
 Temperature
 Velocity of liquid flow in pipelines
 Pressure

March 1-2, 2017 PW AND WFI DESIGN AND OPERATION 24

Temperature
 It is accepted that elevated temperatures can prevent microbial growth, and it
is usual practice for hot WFI systems to operate at 80⁰C
 The value of 80⁰C has been accepted for many years, but lower temperatures
are also effective in preventing microbial growth
 Temperature should be measured at key locations within the storage and
distribution system and at the storage tank vent filter
 Temperature monitoring should cover normal operations and sanitization /
steaming verification

March 1-2, 2017 PW AND WFI DESIGN AND OPERATION 25

Pressure
 Except during times of shut down for maintenance, critical pipeline systems
should be maintained under continuous (positive) pressure, to prevent the
intrusion of any contaminants
 There is no minimum pressure stated in the regulatory guidelines, however
the pressure should be sufficient to:
 Prevent back siphonage from any use point in the system
 Provide adequate pressure for the use points that require a minimum
pressure for consistent operation
 Pressure should be monitored at appropriate locations in the WFI distribution
piping system such as the start and end of the distribution loop

March 1-2, 2017 PW AND WFI DESIGN AND OPERATION 26

Velocity of liquid flow in pipelines
 Flow should be maintained in all portions of the water system at all times, or
provision should be made for automatic flushing of water to drain.
 The actual velocity of the liquid flow is subject to discussion. The currently
accepted velocity of say 5 feet/second (1.5 m/sec) has its basis in being a
practical flow rate for the economic sizing of pipelines, and has little
relationship to the prevention of microbial growth or the formation of biofilm
on the pipeline walls
 In piping systems that continually operate hot, any flow rate that is sufficient
to keep the pipeline full and at the required minimum temperature should be
acceptable
 The flow rate should also be sufficient to displace air from the high points of
the piping distribution system
 In systems that operate at temperatures where microbial growth can occur, a
specific rate of flow will not ensure low microbial levels and other actions,
such as periodic sanitization, are required to provide a suitable operation

March 1-2, 2017 PW AND WFI DESIGN AND OPERATION 27

Conductivity and TOC
 Total Organic Carbon (TOC) and conductivity should be measured at
representative locations in the distribution piping
 TOC monitoring may use a single TOC analyzer for several sample sites with
the samples taken in rotation
 TOC and Conductivity should be measured in accordance with the applicable
compendial requirements
 Temperature compensation in conductivity measuring
 Suitability testing and calibration

March 1-2, 2017 PW AND WFI DESIGN AND OPERATION 28

Controls and Instrumentation
 Critical parameters must be defined
 For critical parameters the monitoring and alarm instrumentation should be
completely separate from the control instrumentation, using different sensors
 Time delays on alarms should only be provided to eliminate alarms caused by
short-term transient conditions. Time delays should not be so long that they
permit significant or intermittent cGMP concerns to be undetected
 Controls and computer systems and PLCs should be GAMP CFR 21 - Part 11
compliant
 Alarm monitoring and reporting should provide for local and remote
reporting, recording and trending capability
 Critical monitoring, recording and alarm components should be on battery
back-up power

March 1-2, 2017 PW AND WFI DESIGN AND OPERATION 29

Sampling
 Water is sampled at the user points for chemical and microbiological quality according to the
relevant SOP
 Sample valves should be provided upstream and downstream of all equipment /components
that can have an effect on the microbial of chemical quality of the critical fluid
 Not all sample points are tested on a routine basis
 Sampling valves must be installed in an easily accessible location
 Sample valve should not be located where the local environment can affect the integrity of
the sample
 Sample valves should be of a design that is suitable for sampling; similar type and size of valve
should be used throughout the system being sampled
 Sampling at locations where hoses are used should be conducted through those hoses, to
replicate actual usage conditions
 Loop outlet valve sample, where the sample valve is upstream of the loop outlet valve, is not
representative of the water supplied to the final point of use
 Sampling at connected equipment should be conducted as close to the final point of use as
practical
 Any flushing performed prior to sampling should use the same procedure that is used for
production use of the water

March 1-2, 2017 PW AND WFI DESIGN AND OPERATION 30

 Operational considerations
 Operating temperature
 Cold
 Ambient
 Hot
 Hot storage – Ambient distribution
 Vent Filter
 Heating
 Replacement
 Integrity testing
 Sanitization - Water systems should be designed to be sanitized
 PW
 Heat
 Ozone
 Chemical ?
 WFI – on the next slide

March 1-2, 2017 PW AND WFI DESIGN AND OPERATION 31

Sanitization WFI
 Sanitization is performed by admitting Pure Steam into the tank and into the
return circulation line to the tank. The isolation valves between the return
line to the tank and the tank outlet to the recirculation line are closed so that
the sanitization steam flows into the tank and around the distribution loop in
parallel separate directions. The steam displaces air and condensate is
removed through condensate traps located at all low points of the pipework.
 At the end of the sanitization process, nitrogen is admitted through the vent
filter to the system so as create a positive pressure during the cooling stage
 The vent filter is sanitized with Pure Steam independently of the rest of the
system. Pure Steam is admitted on the atmospheric side of the filter and
passed through the filter media to the tank side. After sanitization, passing
nitrogen through the filter in the same direction as the steam dries the filter

March 1-2, 2017 PW AND WFI DESIGN AND OPERATION 32

The end of this presentation

March 1-2, 2017 PW AND WFI DESIGN AND OPERATION 33