Principles

• Like any starting material, water must conform to GMP norms & Strengths
• Potential for microbial growth
• Specifications and periodic testing is required
• Systems must be properly validated

Introduction

• Water is one of the five basic elements from which creation emanates
• Pharmaceutical Water is the most widely used ingredient in drug manufacturing and the
main concept in equipment/system cleaning.
• Therefore, systems for the production of pharmaceutical water constitute a key
component in every manufacturing facility.
• The nature of producing pharmaceutical water is to minimize or eliminate potential
sources of contamination.

How to categorize water …

• An Ingredient in a dosage form manufacturing process

• An ingredient in an API with BPC
• Equipment cleaning or rinsing

Types of Water?

• Raw Water
• Potable Water
• Soft Water
• Purified Water
• Sterile purified Water
• Water for Injection
• Sterile Water for Injection
• Bacterostatic Water for Injection
• Sterile water for Irrigation
• Sterile water for Inhalation

Source of Raw Water

• Rain water
• Surface or ground water
• Well or borehole
• Municipal or civil – “tap water”
• Purchased in bulk

WELL Water …

• Inspect exposed parts of the well

• Depth of well
• Nearby septic systems
• Hazardous materials usage (pesticides, fertilizers, etc)
• “Potability”
• Well maintenance

Raw Water Storage

• May be required prior to pre-treatment according to local circumstances

• Check material of construction
• Concrete, steel are acceptable but check corrosion
• Plastics or plastic linings may leach
• Check cover
• To keep out insects, birds and animals
• Check disinfection practices

Why to purify raw water?

• Although reasonably pure, it is always variable

• Seasonal variations may occur in water
• Some regions have very poor quality water
• Must remove impurities to prevent product contamination.
• Control microbes to avoid contaminating products

Contaminants in Water …

• There is no pure water in nature, as it can contain up to 90 possible unacceptable

contaminants
• Contaminant groups:
o Inorganic compounds
o Organic compounds
o Solids
o Gases
o Micro-organisms

Chemical impurities in Water …

• Calcium and magnesium

• Iron and manganese
• Silicates
• Carbon dioxide
• Hydrogen sulfide
• Phosphates
• Copper
• Heavy metals(As, Pb, Cd, etc.,)
• Nitrates

Bio-Impurities in Water …

• Micro-organisms – Biofilm
• Algae
• Protozoa
o Cryptosporidium
o Giardia
• Bacteria
o Pseudomonas
 o Gram negative, non-fermenting bacteria
o Escherichia coli and coliforms

The Influential Circumstances …

Treatment depends on water’s chemistry and contaminants is influenced by –

o Rainfall
o Erosion
o Pollution
o Dissolution
o Evaporation
o Sedimentation
o Decomposition

Key Design Philosophies …

• Purified water system is not only critical from regulatory point of view, but also from
financial point of view. It must be demonstrated that all pharmaceutical waters can be
produced consistently to specifications.
• The plant is designed to produce 0.65 M3/hr product flow rate, the feed water to Reverse
Osmosis plant shall be 1.45 M3/hr, when the following parameters are met.
Parameter Value
pH 7.3
TDS 800-1200
Total Hardness <5
Silica <30
TOC 200
SDI 5-6
• Final treated water quality shall be conductivity-< 20 μs/Cm, TOC - <500 ppb, pH – 5-7.
Key Design Philosophies Continued…

 Operating data for pretreatment (Ultra filtration)

No. of Streams : one number
Feed flow rate : 1350 LPH
Recovery : 90%
Product flow operation : Automatic
Operating Hours : 20 hrs.
 Operating data for R.O. system – I
Attributes R.O. pass – I R.O.pass – II
No of Streams One One
Feed Flow Rate (LPH) 1220 920
Recovery (%) 75% 75%
Product Flow Rate (LPH) 920 685
Operating Pressure (kg/cm2) 13-14 10-11
Types of Operation Semi Automatic Semi Automatic
Operating Hrs 20 20

Key Design Philosophies Continued…

 R.O. Feed Water Limiting Conditions:

Turbidity : <1 NTU
SDI :<3
Heavy metal : Nil
Organics and Bacteria : Nil
Oil and grease : Nil
Total Hardness as Caco3 : <5
Residual chlorine or
Other oxidizable substances : Nil
Temperature : <400 C (Max.)
Colour : Nil
BOD : Nil
COD : Nil

The system shall be subject to sanitization and rectification

if above parameters or water analysis as per the limiting conditions are exceeded.

Water system design

• Pipes sloped so water does not pool and can drain easily
• Sanitary fittings & connections
• Constructed of suitable materials such as stainless steel preferably with low carbon
• Continuous recirculation of the water
• Incorporate non-return valves (NRV) at each….
• Distribution systems with no “Dead Legs”
• Sanitary pumps
• Clamps and O rings vs. threaded fittings
• Heat exchangers
• Side arm level measuring devices are unacceptable

D
Flow direction
If D=25mm & arrows
on pipes are
distance X is important Deadleg
greater than 50mm,
section
we have <2
a dead leg that is too X
D
long.
D=25mm & distance
X is
greater than 50mm,
we have Sanitary
a dead leg that is too Valve
Water scours
long. deadleg
D=25mm & distance X is
greater than 50mm, we have
a dead leg that is too long.

How to purify raw water?

• The most important methods used for the purification of water are:
• Pretreatment of water
• Storage and Distribution of water

Pretreatment

• The step wherein the feed water is made to be of adequate quality to be fed into the final
treatment step.
• Helps to remove non-ionic impurities and cations.
• Feed water to pretreatment quality
• Typical contaminants in feed water includes
 Particulates: Silt, Dust, Pollen, Pipe Scale, Iron and Silica, Undissolved minerals and
organics.
Inorganics: Calcium and Magnesium Salts, Heavy metals (Iron and silica) with their
corresponding ions.
Organics: Naturally occurring by products of vegetative decay.
Bacteria: Bacterial contaminants and their byproducts,endotoxins and pyrogens.

Water treatment purification stages downstream of the pre-treatment system…

• Dis-infection
• Filtration
• Reverse Osmosis and/or De-Ionization
• Distillation or ultra-filtration

Classification of Hardness

Permanent Hardness: This is due to presence of sulphates, Nitrates,

chlorides, carbonates salts of calcium and magnesium.
Removal of permanent hardness either by De-ionization or by
reverse osmosis.
Temporary Hardness: This is due to presence of bicarbonate salts of
calcium and magnesium. Removal of temporary harness is by
thermal treatment only.

Water hardness classification mg/L or ppm

as CaCO3
Soft 0-60
Moderate 61-120
Hard 121-180
Very Hard > 180
Pre-treatment steps

1. Primary filtration and multi-media filter

2. Coagulation or flocculation
3. Desalination
4. Softening

Pretreatment Summary

 Minimizes equipment fouling

 Help in removing turbidity, particulates.
 Removes hardness and metals thus prevents scaling
 Removes of organics and microbiological impurities
 Control of microbial growth and removal of microbial control agents to prevent
degradation of final treatment.

Final treatment steps

A) De-Ionization
B) Reverse Osmosis
C) Electro De-ionization
D) UV-Treatment
E) Ultra Filtration

ION EXCHANGE

 ION EXCHANGE
  Contain cation and anion exchange resin beds (Two Bed type & Mixed Bed type
used as a secondary or a “polishing system”) in a chamber, water is allowed to
pass over these beds, hydrogen and hydroxyl ions are readily removed by
concentration difference.
 Following are the important parameters effecting the capability of the ion
exchange system.
 Resin Quality, Regeneration systems, Vessel Linings, Waste
neutralization systems etc.
 Application: Ion Exchange equipments are used to provide purified water that
satisfies the needs of conductivity as per USP.
 Pretreatment Requirements:
 Undissolved solids should be removed from the water stream.
 Dechlorination of feed water is suggested.

How to Sanitize DI-Unit?

 Can be sanitized using chemical, chemical cleaners include per acetic acid,
sodium hypo chlorite etc.

 Few strong acid cation resins, standard polystyrene cross linked with divinyl
benzene type 1 strong base resin is most suitable for limited hot water
sanitization.

Advantages of Ion-Exchange

 Simple design & maintenance

 Flexible in water flow production
 Good upset recovery
 Low capital cost for single train DI systems
 Removes ionizable and organic substances.

Disadvantages of Ion-Exchange

 High cost of operations on high dissolved solids (TDS) in feed

water
 Requires chemical handling for on-site regenerable DI
 May occupy more floor space
 Requires outside service for offsite systems and are costly
 DI vessels are excellent places for microbial growth.

REVERSE OSMOSIS

 REVERSE OSMOSIS
 It is a pressure driven process, utilizing a semi-permeable membrane capable of
removing dissolved organic and inorganic contaminants from water.
 Semi permeable membrane is permeable to some substances like water,
impermeable to many salts, acids, bases, colloids, bacteria and
endotoxins.
 RO membranes are produced commercially in a spiral wound configuration,
these membranes are available in two basic types.
A) Cellulose acetate and
B) Thin Film Composite(Polyamide).

How to Sanitize RO-Unit?

  Depending on the property of the membrane various chemicals can be used
to sanitize RO unit.

 Specially constructed membranes are used for hot water sanitization at

temperature of 600 to 800 C.

Advantages of RO

 RO units eliminate or significantly reduce chemical handling and disposal relative to

regenarable ion exchange systems.
 RO removes a wide verity of contaminants including ionised solids and nonionic materials
(eg. colloids, Bacteria, Endotoxins and some dissolved organics) .
 Generally RO has more effective microbial control than ion exchange systems
 Integrity testing can be accomplished b salt challenge and measurement of differential
conductivity
 Ro units with proper pH control are general capable of producing water that meets the
requirements of USP (TOC & conductivity)

Disadvantages of RO

 Water consumption is significantly higher than ion exchange system, unless the waste
water is re used.
 Energy consumption is generally higher than ion exchange and less than distillation.
 No removal of dissolved gases (eg: CO2 & NH3)

ELECTRODEIONIZATION (EDI)

The Process which removes ionized or ionizable species from water using
electrically active media and am electrical potential to effect ion transport.
– Formed by two adjacent ion exchange membranes or by a membrane and an
adjacent electrode.purifying cells have permanently charged ion exchange media
between a pair of ion exchange membranes.
 Application:
– Mostly used where drug microbiology is of lesser concern.
– Pretreatment Requirements:
– EDI units should be protected from scaling, fouling, thermal or oxidative
degradation.

Why EDI over Mixed Bed

 EDI offers an environmental alternative

 No regeneration of chemicals.
 Continuous, simple operation
 Reduced facility requirements
 Modular system

How to Sanitize EDI-Unit?

 EDI units are typically chemically sanitized using; per acetic acid, sodium
per carbonate, sodium hydroxide, hydrogen per oxide etc.

Advantages of EDI

 Attainment of stage 1 conductivity

  Elimination of chemical handling
 Cost reduction and economical as not much servicing is required.
 Effective removal of ionizable substances.
 CEDI units may be utilized down stream in reverse osmosis units to produce USP
purified water.
 For USP WFI, CEDI unit may be utilized stream of RO unit.

Disadvantages of EDI

 Cannot remove non-ionic contaminants.

 Design shall be unique for each manufacturer.
 May require additional units for microbial reduction
 May require pretreatment using RO
 CEDI has temperature limitations for practical operations. (Most CEDI units are
operated in the temperature range of 10 – 400C.

ULTRAFILTRATION

The Process which removes ionized or ionizable species from water using
electrically active media and am electrical potential to effect ion transport.
– Formed by two adjacent ion exchange membranes or by a membrane and an
adjacent electrode.purifying cells have permanently charged ion exchange media
between a pair of ion exchange membranes.
 Application:
– Mostly used where drug microbiology is of lesser concern.
– Pretreatment Requirements:
– EDI units should be protected from scaling, fouling, thermal or oxidative
degradation.

How to Sanitize UF-Unit?

 Chemical Sanitizing Agents like Sodium hypo chlorite, Hydrogen peroxide, per
acetic acid, sodium hydroxide and others are used for this purpose.
 Ceramic UF elements can tolerate common chemical sanitizing agents, hot
water, steam and ozone in sanitization or sterilization procedures.

Advantages of Ultra Filtration

 UF membranes are chlorine tolerant, so do not require Dechlorination of feed

water.
 Endotoxins removal can be achieved.
 More cost effective than microfiltration.
 They are more resistant to rigorous sanitization than MF or RO)
 Water stream and energy are consumed in less when compared to others.

Disadvantages of Ultra Filtration

 Not possible to remove ionic contaminants.

 UF generally requires a waste stream, which can be a cost factor
 UF membranes integrity testing is more difficult than other filters and cartridges

Dis-infection (UV Treatment)

Mostly Done to Render the Water Free From Microbes

UV (254nm) does not “sterilize”, it only reduces bio load

Things to be Consider:
 o Flow rate critical
o Lamps have finite life

Advantages of UV treatment

 Simple in design & Maintenance (254 nm for microbe reduction & 185 nm for
TOC reduction)

 No waste steam required

 Heat, ozone and chemical sanitization are possible

Disadvantages of UV treatment

 No ion or endotoxins removal

 Particulates can shield the UV light, rendering microbes unharmed.

 Used only as a safety net for microbial production

Instrumentation and Control

All instruments and control systems are believed to comply with GEP and are required to
be qualified.
 Generally used along with Water systems:
-To Control the operation of Equipment and components
-To Monitor and Document the Performance of
critical equipment.
-To monitor and document the Pharma. Water
Quality
Instrument Selection and Installation:
 Instruments shall be installed as per manufacturers specs.
 Should possess accuracy and reliability over entire process range.
 Should be installed to prevent contamination.
 Instruments may be installed with auxiliary sensors to check water quality.
 Accessibility for maintenance shall be considered.
 Instrument Calibration:
 Regular program shall be followed for calibration of critical instruments.
 Calibrate as per approved procedures.
 Vendor supplied calibration certificates shall be documented and shall refer the
applicable instrument serial number.

TYPES OF INSTRUMENTS
 Conductivity
 Total Organic Carbon (TOC)
 pH & Ozone detecting
 Flow meters
 Temperature
 Pressure
 Level indicators etc.

Control Systems (SCADA)

Selection of the control strategy for Pharma Ware systems shall consider feed water
quality & reliability, complexity in purification & distribution system, labor costs, personnel skill
levels and capabilities etc. control systems shall be of following categories…
 a) Local Instrumentation with Manual controls,
b) Semi-Automatic control,
c) Automatic Control & Fully Integrated systems.

Sampling

Extensive sampling is required to establish and confirm that the entire system will
operate within specified limits, to develop and evaluate the system operation and maintenance
procedures, and to verify the water produced is within specified limits.
1. There must be a sampling procedure
2. Sample integrity must be assured
3. Sampler training
4. Sample point
5. Sample size
6. Sample container
7. Sample label
8. Sample storage and transport
9. Arrival at the laboratory
10. Start of test

Testing - setting specifications for purified water

Test Limits
EP USP-XXV IHS
Description Clear, Colorless , Clear, Colorless Clear, Colorless
Odorless, tasteless liquid and odorless liquid and odorless liquid

pH - 5–7 5–7
Conductivity NMT 4.3 µ s-cm- NMT 1.3 µ s-cm- NMT 1.3µ s-cm-
1 1 1
TOC NMT 500 PPB NMT 500 PPB NMT 500 PPB
Nitrates 0.2 PPM - 0.2 PPM
Heavy Metals 0.1 PPM - 0.1 PPM
Total Viable Aerobic Count 100 CFU/ml 100 CFU/ml 100 CFU/ml

Pathogens Salmonella, E.Coli, Pseudomonas, S. Aureus etc shall be absent.

Testing

Method verification
l Chemical testing
– test method
– types of reagents used
l Microbiological testing
– types of media used
– incubation time and temperature
– objectionable and indicator organisms
– manufacturer must set specifications
– Water for final rinse must be of the
same quality as the water required
for pharmaceutical preparation
 Suggested bacterial limits (CFU /mL)

Sampling location Target Alert Action

Raw water 200 300 500
Post multimedia
100 300 500
filter
Post softener 100 300 500
Post Ultra Filtration 50 300 500
Feed to RO 20 200 500
RO permeate 10 50 100
Points of Use 1 10 100

Inspection of water system:

 FDA looks for

– Water Quality Manual
– Water system drawing
– Validation of water treatment system (IQ, OQ, PQ)
– Specifications and trends
– Planned maintenance, sanitation and monitoring activities
– Controlled procedures to prevent microbial growth

FDA will check for…

 Dead legs
 Filter
 Pipes and fittings
 Storage tanks
 By-pass lines
 Pumps
 UV lights
 Sample points
 RO
 Non return valves / Diaphram valves / Vent filters
 Heat exchangers
 Hygienic couplings
 Welded pipes
 Hygienic pumps
 Hygienic
 Sampling points
 Acceptable floor
 Leakages

Additional things, FDA looks for…

 1. Sanitization efficacy against Bioload
2. Temperature-compensated conductivity meters
3. Polypropylene welding inspection
4. checking pin holes
5. Retrospective validation of WFI system
6. Rouging of WFI storage systems
7. Spray ball efficacy
What is Bio Film

Biofilm formation
1. Free swimming aquatic bacteria use polymucosaccharides to colonise surfaces
2. Complex communities evolve which shed micro-colonies and bacteria

Nature of the Non-Conformance:

Water from the RO storage tank is stored in a Feed tank and pumped to the still.The water is
ambient and static in the feed tank, booster pump and a portion of pipe leading to the still. The
static portion of the water system from the RO Storage tank to the still has never been validated.

Required Preventive Actions

 As part of PQ, flow details, areas where stagnation is possible, should be well
identified, the risk of contamination is not evaluated.

 All critical areas should be well monitored for bio load along with User Points.

Nature of Non-Conformance
Failure to conduct periodic review of the various computer control systems performance,
changes and configuration control. There is no procedure for annual reviews of all Computer
systems and the need of requalification is to be established.

Required Preventive Actions

 After completing the UAT, Firm should ascertain the procedure for performance
and configuration control of computer systems.
 An effective preventive maintenance programme for computer systems should be
implemented.
 The performance, discrepancies and changes in the version as well as
components of computer systems must be recorded in the respective history cards
along with actions taken.
Nature of Non-Conformance
The sterile vent filter is required to be integrity tested semi- annually and changed annually.
There is no record of the semi-annual integrity testing of this filter.Management stated that this
filter is integrity tested and changed annually. During the annual maintenance, this filter failed
integrity testing

Required Preventive Actions

 Procedure for integrity testing and replacement of various filters must be well
established by considering the manufacturing recommendations.
 An effective implementation programme should be established

Nature of Non-Conformance
The UV Sanitizers(Bulbs) are to be changed annually and the sleeves are to be cleaned semi-
annually. There is no record of the semi annual cleaning of the sleeves, nor is there any record of
the microbial kill effective ness of the ultraviolet light sanitizers.

Required Preventive Actions

 Effective Procedures must be established for monitoring, replacement, cleaning of

UV lamps.
 The detailed cleaning procedure must be established by considering the areas
where there is a chance of microbial contamination.
 Efficacy evaluation of bio load must be monitored before and after the UV unit at
regular intervals.

Nature of Non-Conformance
A malfunctioning meter on a UV light located on the water system was not fixed for six weeks
because the supervisor not notified, and a second malfunctioning meter was not fixed for five
weeks.
Required Preventive Actions

 Effective training
programme to be imparted to all the working personnel with clear awareness towards all
critical instruments working condition and their functioning.
 A Daily checklist which is
covering all the sections of the water system must be maintained
 Efficacy evaluation of bio
load must be monitored before and after the UV unit at
regular intervals.

THERE ARE SIX HONEST SERVING MEN WHO HELP US IN ALL WE DO

 WHERE?

WHY?

“SHOW ME”
AUDITORS

WHO? HOW?

WHEN?

Validation
• Water system shall be subjected to planned maintenance and validation
• There may be several ways to perform validation of a water system.
• Description of system along with equipment and drawings showing all the points from
feed to point of use.
• All the sampling points and their designations
• The drawings should be compared with the actual system at least once a year to ensure
its accuracy, to detect un-reported changes and to confirm reported changes.
• A data demonstrating that SOPs are current and valid
• A data to support that seasonal variations in the feed water do not adversely affect the
operation of the system or the water quality

Validation phase I

Verification of DQ & IQ
• Development of operational parameter, cleaning procedures, sanitization procedures and
their frequencies
• During validation phase sampling should be daily at each point of use for minimum two to
four weeks
• The sampling procedures should reflect how the sample is to be drawn e.g. if SOP
indicates that the point of use or hose is to be flushed for 10 minutes or so, the sample is
to be drawn after that flush
• At the end of 2-4 weeks period SOP may be developed for water system

Validation phase II

To demonstrate that the system will consistently produce the desired water quality when operated
in accordance with SOPs
• The sampling is performed as in the phase I and for the same period.
• At the end of this phase the data should demonstrate that the system would consistently
produce the desired quality of water
 Validation phase III

This is designed to demonstrate that when the system is operated in accordance with the SOPs
over a long period of time, it will consistently produce the water of desired quality
• Any variation in the quality of feed water that could effect operation is to be studied in this
phase
• For WFI systems, the sample should be taken daily from one of the point of use with all
the points of use are tested weekly. This phase is complete when the firm has data for full
year.

Validation - few concepts

• A problem could be faced to preclude contamination of water system with non-sterile air
remaining in a pipe after drainage and there will be higher microbial contamination. This
should be studied and avoided
• WFI is to be essentially sterile, since the sampling frequently is performed in non-sterile
areas and the sampling is not truly aseptic, less that 10 CFU/100 ml is an acceptable
action limit.
• In WFI all limits are action limits and not pass / fail limits.
• Sample size should be 100-300 ml and any volumes less than this should not be
accepted for study
• Higher CFU limits are permitted for Purified Water systems and action limits should be
established.
• The purpose of establishing any action limits is to assure that the water system is under
control.
• Objectionable organism should be identified as specific contaminant rather than the
number
• Identifying organism is generally more significant for designing controls
• Organisms exist in a water system either as a free floating in the water or attached to the
walls of the pipes and tanks.
• When they are attached to the walls they are called “biofilms”.

Bio-film contamination

• Thus contamination is not uniformly distributed in a system. A count of 10 in one sample

and 100 – 500 in another may not be unrealistic

Water for Pharmaceutical Use

Qualification
• WPU systems are "direct impact systems"
• Therefore stages to be considered in qualification should include DQ, IQ, OQ, PQ
• DQ: Design review influenced by source water and required water quality
• IQ: Installation verification of the system
• OQ: operational qualification
• Presentation focusing on PQ
• PQ demonstrates consistent and reliable performance of the system
• Three phase approach recommended over extended period – proves reliability and
robustness

Phase 1 (1)
• A test period of 2–4 weeks - monitoring the system intensively
• System to operate continuously without failure or performance deviation
The following should be included in the testing approach:
• Undertake chemical and microbiological testing in accordance with a defined plan

Phase 1 (2)
• Sample daily:
 incoming feed-water
  after each step in the purification process
 each point of use and at other defined sample points
• Develop:
 appropriate operating ranges
 and finalize operating, cleaning, sanitizing and maintenance procedures

Phase 1 (3)
• Demonstrate production and delivery of product water of the required quality and quantity
• Use and refine the standard operating procedures (SOPs) for operation, maintenance,
sanitization and troubleshooting
• Verify provisional alert and action levels
• Develop and refine test-failure procedure

Phase 2 (1)
• A further test period of 2–4 weeks – further intensive monitoring the system
• Deploying all the refined SOPs after the satisfactory completion of phase 1
• Sampling scheme generally the same as in phase 1
• Water can be used for manufacturing purposes during this phase

Phase 2 (2)
Demonstrate:
• Consistent operation within established ranges
• Consistent production and delivery of water of the required quantity and quality when the
system is operated in accordance with the SOPs.

Phase 3
• Over one year after the satisfactory completion of phase 2
• Water can be used for manufacturing purposes during this phase
Demonstrate:
 extended reliable performance
 that seasonal variations are evaluated
• Sample locations, sampling frequencies and tests should be reduced to the normal
routine pattern based on established procedures proven during phases 1 and 2

Ongoing system monitoring

• After Phase 3 – system review needed
• Based on review including results, establish a routine monitoring plan
• Monitoring to include a combination of on-line monitoring and off- line sample testing
• Data analysed for trends

Ongoing system monitoring (2)

• Monitoring parameters to include:

 flow, pressure, temperature, conductivity, TOC
• Samples taken:
 From points of use, and specific sample points
 In a similar way how water is used in service
• Tests to include physical, chemical and microbial attributes

Validation - few concepts

• The “dead-legs” could be described as “not having an unused portion greater in length
than six diameters of the unused pipes from the axis of pipe in use”.
 This description is more suited to 75-80° circulating system.
• With colder systems any drops or un-used portion on any length of piping has the
potential for formation of a bio-film and should be eliminated having special sanitizing
procedures
• There should be no threaded fittings in a pharmaceutical water system. All pipe joints
must utilize sanitary fittings or be orbital/robotic welded
• Sanitary fittings will usually be used where the piping meets the valves, tanks and other
equipment, which should be removed for maintenance or replacement.
• The procedure for sanitization should be reviewed and evaluated.

Concluding

• An adequate PW system using filtration may be:

 UG Storage tank ] Chlorination ] Sand filter ] carbon filter ] RO ] Mixed Bed
(Polishing bed, with routine resins) ] Storage in Tank ] UV Lamp ] Circulate ] Use
for production.
• A good validated system may include
 UF after pretreatment ] double pass RO installed in series ] supported by
electronic de-ionization (EDI)
• And WFI system
 PW ] Distillation ] Storage ] Circulation ] (Heat Exchanger or Line Coolers) ] Use
for production