pw and wfi storage and distribution systems design and...

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


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


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



◦ 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)

Applicable standards

Use of Water


Uses PW WFI

Feed water √ -

Washing √ √

Final rinse √ √

Formulation √ √

Humidification √ Pure Steam

Others (e.g. USP 1231)

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

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


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


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


Storage tank

Proper sizing

Rupture disk

Double jacket


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


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)


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


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


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


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.


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


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


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


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


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


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


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


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


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


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


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


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


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


The end of this presentation


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