Pharmaceutical Water Systems

Pharmaceutical Water System

I Basic Regulatory Requirements
II Water Quality Requirements
III Water System Planning
IV cGMP Requirements and design
Consideration
V Microbiology of water
VI Deionization / Electro-deionization
VII Purified Water System Design
VIII Water for Injection Production
Techniques
IX Reverse Osmosis
X Storage and Distribution Installation
Considerations
XI Ozone Bio-contamination Control
XII System Materials and Finished
XIII Commissioning and Validation
XIV System Maintenance & Troubleshooting
USP Summary for Bulk Waters
USP WFI shall be produced by distillation or proven
validatable equivalent methods.
The USP requires that Purified Water and Water for
Injection meet specific conductivity <645> and
TOC<643> requirements.
USP <645> is a 3 stage conductivity test. It permits
on- line and off line testing. <645> requires the use
of non-temperature-compensated conductivity
measurement. <645> requires specific performance
requirements for the instruments.
<643> permits on-line and off-line testing.
Conductivity and TOC Requirements for USP Bulk
waters and very mature and little will change.
EP Summary for Bulk Waters
EP WFI shall be produced by distillation. Other
methods NOT accepted.
EP requires that Purified Water and water for Injection
meet specific conductivity (2.2.38) and TOC (2.2.44)
requirements. Nitrates and Heavy Metals testing still
required. EP conductivity testing has weaknesses in its
design: no on- line testing, faulty calibration, lack of
instrument QC requirements.
Conductivity requirement are changing in 2004. WFI
& WH-P conductivity to look like USP requirement.
PW conductivity to be changed to allow on-line, but
un-harmonized.
TOC testing fully harmonized with USP.
EP microbiology limits harmonized, but written as
part of monograph.
Packaged Water Summary
Packaged Water requirement need revision by
all groups.
USP has 9 chemistry tests for Sterile Water for
Injection (SWFI), after preparing WFI!
USP plans to reduce to 2 test
- Conductivity (same limits as EP?)
- Quantitative organic analysis test (TOC or
spectrophotometric)
EP has ~ 15 wet chemistry tests for SWFI,
plus conductivity
I. Basic Regulatory Requirements
Understand regulatory requirements
Pharmacopoeias
Rules and Guidance (GMP)
Regulatory Bodies
Origin and development of water
quality requirements
The Pharmacopoeia
Important statutory component of an
overall system of control of medicinal
products
Complements and assists licensing
and inspection processes
Separate for USA (USP) and Europe
(Ph. Eur., BP)
European Pharmacopoeia (Ph. Eur)
Fourth Edition (Yearly supplements)
Supported by Pharmeuropa
Used Internationally
Legally enforceable
United States Pharmacopoeia (USP)
USP 28
Supported by Pharmacopeial Forum
Sets drug standards but cannot enforce
Used Internationally
Monographs are a legal requirement
General Information Not legal
requirement
USP 28
General Information
<6D dead legs
sloped piping lines
complete drain ability
no pockets
sample valves
sanitization
installation and materials of construction
Rules and Guidance (GMP)
Rules Governing Medicinal Products in
the European Community (Commission of
the European Communities)
Code of Federal Regulations (CFR) Title
21 (Food and Drug Administration)
Regulatory Bodies
European Medicines Evaluation Agency
(EMEA)
Agencies in member nations
e.g. Medicines Control Agency (MCA)
from April 1
st
2003 Medicinal and
Healthcare products Regulatory Agency
(MHRA)
Food and Drug Administration (FDA)
Enforcement
Regulatory bodies legally enforce drug
standards
Safety
Efficacy
Strength
Purity
Enforcement (2)
Pharmacopoeias set drug standards but
cannot enforce them
MHRA/FDA enforce drug standards but
cannot set them
There are many grey areas open to
interpretation by different regulators
Good Manufacturing Practices
If the manufacture or control procedures
do not conform to cGMPs
Regulators may deem products to be
adulterated
Manufacturer may be subject to
regulatory sanctions
Regulators do not have to find products
actually contaminated before instituting
sanctions
Current Good Manufacturing
Practices (cGMPs)
Regulators enforce adherence to cGMPs
Production could be stopped
Recalls might be required
Submissions may be delayed
Importations could be stopped
Adulterated products could be seized
Common Concerns of the Regulator
poor microbial control
poor water quality test procedures
poor SOP adherence
lack of trending and validation
Drug Manufacturer Responsibilities
Define appropriate water purity
Process requirements
regulatory requirements
each process step
all critical parameters chemical,
physical and biological
Demonstrate that all waters can be
produced consistently to specification
Good Engineering Practice
Build to plans and specifications.
Inspect, test and document.
Minimum level documentation.
Design Fabrication Vendor testing
Construction Field Inspection
Commissioning
Good Engineering Practice
Documents can support commissioning
and validation
Proper planning
Proper organization
Proper authorization
Pharmaceutical Water Compendial Types
Bulk forms
Purified Water (PW)
Water Highly Purified (WHP)
Water for Injections (WFI)
II. Water Quality Requirements
Packaged Forms
Bacteriostatic WFI
Sterile Water for Inhalation
Sterile Water for Injections
Sterile Water for Irrigation
Purified Water in Containers
Pharmaceutical Uses for Water
Constituent
Production Process
Wash equipment / product
Cooling
Steam for sterilization
USP 28
Source water defined
Distillation or RO
Conductivity 3 Stages
TOC 500 ppb
BET 0.25 EU/ml
Micro count 10 cfu/100 ml
(guideline <1231>)
WFI Requirements
EP 4
th
Edition 2002
Current WFI Requirements
Source water defined
Distillation only
Conductivity (1.1 S@20
O
C)
TOC 500 ppb
Additional tests for Nitrate(max.0.2ppm), Heavy Metals
(max.0.1ppm)
BET 0.25 IU/ml
Micro count 10 cfu/100 ml (200 ml minimum)
Aluminium (max. 10 ppb,Dialysis only)
USP 28
Purified Water Requirements
Source water defined
Suitable process
Conductivity 3 Stages
TOC 500 ppb
Micro Count 100 cfu/ml
(guideline <1231>)
EP 4
th
Edition 2002
Purified Water Requirements
Source water defined
Suitable process
Conductivity (4.3S@20
O
C)
TOC 500 ppb (or Oxidisable substances)
Additional tests for Nitrate, Heavy Metals
Micro Count 100 cfu/ml (suitable sample size)
BET and Aluminium (Dialysis only)
USP/EP Differences for WFI
Distillation
Conductivity Limits
Nitrate, Heavy Metals
Aluminium
USP/EP Differences for Purified
Water
Conductivity Limits
Oxidisable Substances
Nitrate, Heavy Metals
BET and Aluminium
Conductivity Test (theory)
Conductivity increases as function of temperature
Conductivity varies as function of pH
Change in conductivity varies with different ions
Must be determined by non temperature
compensated meter
Stage 1 allows on line measurement
Stage 2 laboratory test
Stage 3 closely controlled pH and temperature
USP Conductivity Test
Stage 1 Temperature and Conductivity Requirements
(for nontemperature-compensated conductivity measurements only)
Temperature Conductivity Requirement (S/cm)
0
5
10
15
20
25
30
35
40
45
50
55
60
65
70
75
80
85
90
95
100
0.6
0.8
0.9
1.0
1.1
1.3
1.4
1.5
1.7
1.8
1.9
2.1
2.2
2.4
2.5
2.7
2.7
2.7
2.7
2.9
3.1
If the conductivity is higher than the table value, proceed with Stage 2.
Stage 2
Transfer a sufficient amount of water (100 ml
or more) to a suitable container, and stir the test
specimen. Adjust the temperature, if necessary,
and while maintaining it at 25 1
0
, begin
vigorously agitating the test specimen while
periodically observing the conductivity. When
the change in conductivity (due to uptake of
atmospheric carbon dioxide) is less than a net of
0.1 S/cm per 5 minutes, note the conductivity.
If the conductivity is greater than 2.1 S/cm,
proceed with Stage 3.
Stage 3 pH and Conductivity Requirements
(for atmosphere and temperature equilibrated samples only)
pH Conductivity Requirement (S/cm)
5.0
5.1
5.2
5.3
5.4
5.5
5.6
5.7
5.8
5.9
6.0
6.1
6.2
6.3
6.4
6.5
6.6
6.7
6.8
6.9
7..0
4.7
4.1
3.6
3.3
3.0
2.8
2.6
2.5
2.4
2.4
2.4
2.4
2.5
2.4
2.3
2.2
2.1
2.6
3.1
3.8
4.6
If either the measured conductivity is greater than this value or the pH is outside the range of
5.0 to 7.0, the water does not meet the requirements of the test for conductivity.
Conductivity
Agreed replacement for wet chemistry
Theory and model similar in US and Europe
Detailed application very different
EP differs for WFI and PW
No on-line provision in EP
Different temperatures
EP retains Nitrates
EP Conductivity
EP introduced conductivity in 1999 (2.2.38)
Difficulty complying, several anomalies
Not designed for on-line testing
States use platinum electrodes (not optimal)
Temperature compensation unclear
Lack appreciation of CO
2
equilibrium
EP update expected
Harmonization for Conductivity Limits
USP <645> has two tables of conductivity limits
- Permits on-line test from 0 - 100
o
C.
- Permits off-line tests and accounts for
innocuous CO
2
at 25
o
C.
EP 2.2.38 has two conductivity limits
- 1.1 S/cm at 20
o
C for WFI
- 4.3 S/cm at 20
o
C for Purified Water.
- Retain nitrate test.
- Retain Heavy Metals test.
10.0
9.0
8.0
7.0
6.0
5.0
4.0
3.0
2.0
1.0
0
0 10 20 30 40 50 60 70 80 90 100
Temperature (
o
C)
Proposex1 EP WFI Limits
U
n
c
o
m
p
e
n
s
a
t
e
d

c
o
n
d
u
c
t
i
v
i
t
y
,

s
i
0.8
0.9
1.0
1.1
1.3
1.4
1.4
1.7
1.8
1.9
2.1
2.2
2.4
2.5
2.7 2.7 2.7 2.7
2.9
3.1
TOC
TOC = Total Organic Carbon
Non-purgeable organic carbon
Replacement for Oxidisable Substances
Introduced USP 1996
Introduced EP 1999
Previously in JP
TOC EP vs USP (1)
Common limit (500 ppb)
Methods very similar
Organics completely oxidised to CO
2
Organics compounds oxidise at different rates
Calibration uses easy to oxidise (sucrose)
and difficult (1,4-benzoquinone)
On-line or Laboratory measurements
TOC EP vs USP (2)
EP reagents cheaper (Reagent grade)
Common limit for PW and WFI
EP allows oxidisable substances for PW
EP reagent water conductivity limit 1.0Si at
25
O
C
Only minor differences, satisfactory
Microbiological Requirements
Water for Injection
USP 28 10 cfu/100 ml (<1231>)
0.25 EU/ml
Distillation or RO
EP 4
th
(2002) 10 cfu/100 ml (min 200 ml)
0.25 IU/ml
Distillation only
Method for Production
WFI only Pharmacopoeial product assigned
a specific method of production in addition
to specified quality.
Pharmaceutical only industry to use
distillation to prepare high purity water.
European regulators adamant that
distillation is only acceptable method for
WFI production.
Microbiological Requirements
Purified Water
USP 28 100 cfu/ml (<1231>)
Suitable method
preparation
EP 4
th
(2002) 100 cfu/ml (suitable
sample)
BET (dialysis) Suitable
method preparation
Water Highly Purified
Latest Grade From EP and BP
Intermediate between PW and WFI
Low Endotoxin requirement
Introduced January 2002
Ph Eur 4
th
Edition (2002)
Water, Highly Purified
Source water as for PW and WFI
For medicinal products where water of high
biological quality is needed, except where
WFI is required
Manufacture relaxed, permits RO with ultra-
filtration and deionisation (as example)
Chemical & Micro testing as for WFI with
same limits
Choice of Water Quality
Consistent with final product requirements
WFI minimum quality for parenteral drug
ingredient
Purified Water minimum quality for oral dosage
ingredient
Must establish logic for quality based upon end
product
III. Water Planning
Process Water
Manufacturing Water used for
Non Sterile Products Sterile Products
No No Yes Yes
Downstream
Processing
Parenteral
Product
WFI PW PW WFI
Cleaning Water
Cleaning Water used for
No Yes
Final
rinse
Suitable
non compendial
water
Use same water
as processing /
manufacturing
* Non compendial water comparative to potable water
(microbial)
Water Decision Considerations
Drinking Water may be used in the early stages
of chemical synthesis and in the early stages of
cleaning of pharmaceutical manufacturing
equipment USP
Water with tighter chemical and microbial
specifications should be used in later processing
steps or if the impurities are unable to be
removed in later steps FDA Guide for
Manufacturing, Processing, or Holding Active
Pharmaceutical Ingredients
Microbial Level Establishment
Alert and action levels required
Compendial and non-compendial waters
Levels for non-sterile products
product
potential harm to user
Levels based on process needs and
historical record
Microbial Level Establishment
Can microorganisms threaten product
preservation or stability?
Can product be contaminated with
pathogens or endotoxins?
Maximum action levels
WFI : 10 cfu/100 ml
PW : 100 cfu/ml
Drinking water : 500 cfu/ml
IV. cGood Manufacturing Practices
Series of rules ensuring that
pharmaceutical products are manufactured
in a CONSISTENT and CONTROLLED
manner and will be FIT for their intended
purpose
GMP maintains a Companys reputation
and product integrity.
GMP Requirements
General
Provide guidance
Need to be applied according to local conditions
Used in conjunction with pharmacopoeial
requirements and registered details as basis for
inspection
Industry norm
continuous progression
European GMP (1)
A1.31
Water treatment plants should be
designed, constructed and maintained so as
to ensure the reliable production of water
of an appropriate quality. They should not
be operated beyond their designed
capacity. Water should be produced stored
and distributed in a manner which prevents
microbial growth, for example by constant
circulation a temperature above 70C
European GMP (2)
A1.30
Water treatment systems including stills
should be subject to planned maintenance
and validation, their use following
maintenance work should be approved by
Quality Control
European GMP (3)
A1.40
Water sources, water treatment equipment
and treated water should be monitored
regularly for chemical and microbiological
contamination and, as appropriate, for
endotoxins. Records should be maintained
of the results of the monitoring and of any
action taken
European GMP (4)
3.4.3
Distilled, deionised and, where
appropriate, other water pipes should be
sanitised according to written procedures
that detail the action limits for microbial
contamination and the measures to be
taken
European GMP (5)
A9.4
After any chemical sanitisation of the
water systems, a validated flushing
procedure should be followed to ensure
that the sanitising agent has been
effectively removed
USA GMP
21 CFR Part 210 Interpretation
Pharmaceutical waters used in the
manufacture of drugs or drug products
are subject to the regulations of the
cGMPs whether or not the water remains
in the final product
USA GMP
21CFR Part 211.48a
Potable water shall be supplied under
continuous positive pressure in a
plumbing system free of defects that
could contribute contamination to any
drug product. Potable water shall meet
the standards prescribed in the EPAs
Primary Drinking Water Regulations
USA GMP
21CFR Part 211.48b
Drains, where connected to a sewer,
shall be provided with an air break
Of particular concern on sanitisation
or product divert lines
Air breaks preferred to check valve or
backflow preventers
Common drains should be scrutinised
to ensure there is no possibility of
back contamination
USA GMP
21CFR Part 211.65a
Surfaces that contact components, in
process materials, or drug products shall
not be reactive, additive, or absorptive so
as to alter the safety, identity, strength,
quality, or purity of the drug product
21 CFR 211.65a Interpretation
Opens all process water contact surfaces
to FDA scrutiny
Implies use of inert materials for product
water handling
Manufacturer must prove suitability of
system components and materials
USA GMP
21CFR 211.65b
Any substances required for
operation, such as lubricants or
coolants, shall not come into contact
with components so as to alter the
safety, identity, strength, quality, or
purity of the drug product beyond the
official or other established
requirement
21 CFR 211.65b Interpretation
May imply the use of :
Double containment heat exchangers
Leak detection systems
Process water pump flush seals
Atmospheric air hydrophobic vent filters
Suitable nitrogen and ozone
USA GMP
21CFR 211.67b
Equipment shall be cleaned,
maintained, and sanitised at
appropriate intervals to prevent
malfunctions or contamination that
would alter the safety, identity,
strength, quality, or purity of the drug
product beyond the official or other
established requirement
21 CFR 211.67a Interpretation
Routine maintenance plans required for
all equipment
Individual unit monitoring required
Sanitisation frequency dependent on
product water quality requirements and
system design
21 CFR 211.67a Further Interpretation
Opens equipment rinse water to review
Rinse water should be free from objectionable
contaminants
Final rinse water shall be of equal quality to
manufacturing water
Final rinse for parenteral production could be
interpreted to be :
WFI
WFI equivalent (e.g. by ultrafiltration)
USA GMP
21CFR 211.67b
Written procedures shall be
established and followed for cleaning
and maintenance of equipment
SOP required for operation and
maintenance of pharmaceutical water
systems
USA GMP
21CFR 211.67c
Records shall be kept of maintenance,
cleaning, sanitising, and inspection
Sanitisation, cleaning, and
maintenance procedures shall be
documented
Sanitisation and cleaning performance
shall be validated and records shall be
maintained
21 CFR 212 Proposals
Filters may not be used at any point in the
water for manufacturing or final rinse piping
system
No point-of-use filters
No filters present in the distribution loop
Filters cannot be the terminal process of the
generation system
Consistent with the requirements for WFI
Considered cGMP
21 CFR 212 Proposals
Pipelines for the transmission of water for
manufacturing or final rinse and other liquid
components shall be constructed of welded
stainless steel equipped for sterilisation with
steam
Assumed applicable only to product water
Some validated systems utilise plastic
piping to minimise contaminants for
product specific applications
21 CFR 212 Proposals
Pipelines for the transmission of water for
manufacturing or final rinse and other liquid
components shall be sloped to provide for
complete draining
Assumed applicable to final product water
only (sanitary piping) for steam sanitised /
sterilised systems
Complete system drainability not always
utilised for hot water and chemically
sanitised systems
21 CFR 212 Proposals
Pipelines for the transmission of water for
manufacturing or final rinse and other liquid
components shall not have unused portion
greater in length than six diameters of the
unused pipe measured from the axis o the pipe
Minimal deadleg is GMP requirement
Debate over 6D measurement
Current consensus <4D, ideally none
21 CFR 212 Proposals
The integrity of all air filters shall be verified
upon installation and maintenance throughout
use
Applicable to membrane filter elements for
storage tank vent filtration
Considered a cGMP requirement
21 CFR 212 Proposals
Heat exchangers, other than the welded
double concentric tube type or double tube
sheet, must employ a pressure differential and
a means for monitoring the differential
Applicable to sanitary heat exchangers and
condensers
Considered a cGMP requirement
21 CFR 212 Proposals
All stills and tanks holding liquid requiring
microbial control shall have air vents with
non-fiber-releasing sterilizable filters capable
of preventing microbial contamination of the
contents
Applicable to product water storage tanks
Opens nitrogen quality to scrutiny in
nitrogen blanketing system
Considered a cGMP requirement
21 CFR 212 Proposals
Pumps moving water for manufacturing or
final rinsingshall be designed to utilize
water for injection as a lubricant for the seals
Common cGMP practice for WFI
21 CFR 212 Proposals
Water used as a component of as a final rinse
for equipment or product contact surfaces
shall conform to the specifications in the USP
for Water for Injection
WFI quality water validated for final rinse
in some parenteral facilities
Allows consideration of UF as terminal
process
21 CFR 212 Proposals
Water used as a component of as a final rinse
for equipment or product contact surfaces
shall be stored in a suitable vessel or system
including a piping network for distribution to
points of use at a temperature of at least 80C
under continuous circulation or at ambient or
lower temperatures for not longer than 24
hours, after which time such water shall be
discarded to drain
21 CFR 212 Proposals
Feedwater for boilers supplying steam that
contacts components, in-process materials,
drug products, and drug product contact
surfaces shall not contain volatile additives
such as amines or hydrazines
Steam sampling program required
Pure steam generators required for steam
sanitisation of sanitary process equipment
Current cGMP requirement
Common Regulatory Concerns
Water Systems not adequately validated
Testing not representing worst case (eg.
sampled after sanitisation)
Lack of written procedures
Failure to follow SOPs (eg. Maintenance)
Lack of adequate staff
Unapproved, unjustified changes to systems
Lack of Trending
Specific cGMP Design
Considerations
System validation
Consistent attainment of product water quality
NIST Calibratable Instruments for critical
parameters
Ability to sanitise all system components
Specific cGMP Design
Considerations
Documentation of material suitability
Accurate documentation for all assemblies,
installations, operation and maintenance
Appropriate piping joint methods
Minimal stagnant areas
Minimal deadlegs
Specific cGMP Design
Considerations
Product water storage vent filtration
Still condenser vent filtration
Double containment heat exchangers or
appropriate pressure differential
V. Microbiology Requirements
EP limits are ACTION LIMITS in Production section
- Purified Water100 cfu/ml
- WFI..10 cfu/100 ml
USP limits are recommended in <1231> general chapter
- Same limits as EP
JP limits are enforced in drinking water requirements
- Same limits as EP
In practice, this is the most widely audited and
monitored attribute of PW and WFI.
Endotoxin Requirements (WFI only)
< 0.25 EU/mL Endotoxin (USP and JP)
< 0.25 IU/mL Endotoxin (EP)
Same limits and same tests.
Alert Levels
Alert - Exceeded indicate process may be
drifting from normal operation
- Earning - not necessarily requiring
correction
- Demanding based on historic data
- Constantly reviewed
Action Levels
Action - Exceeded indicate process has
drifting from normal operation
- Corrective action requiring
- Often based on Regulatory
Guidelines but should also take
account of local situation
Typical Industry Water Testing
Approach for Bioburden
Water Method Frequency Limit
Potable
Purified
WFI
Pour Plate
Membrane
Pour Plate
Membrane
Pour Plate
Membrane
3 Months
Weekly (70%)
Daily (90%)
Absence of
specific
organisms
500 cfu/ml
100 cfu/ml
10 cfu/100ml
VI. De-ionisation/Electro de-ionization
Ion Exchange
Conversion of to acids by hydrogen
cation exchange
Removal of acids by anion exchange
Cations(+) and anions(-) in solution in
neutrality
Cation Exchange Resin
Immobile anionic radical exchange sites
(e.g. SO
3
)
Mobile cation attached (e.g. H
+
.
Na
+
,Ca
++
)
In neutrality with solution one Ca++
replaces two H
+
Cation Exchange Resin
Made of organic compound polymers (e.g.
styrene, di-vinylbenzyne)
Regenerated with acid (e.g. HCI, H
2
SO
4
)
There are Strong acid and Weak acid
types
Anion Exchange Resin
Immobile cationic radical exchange sites
(e.g. quaternary ammounium)
Mobile anions attached (e.g.
OH,CI,SO
4
=
)
Regenerated with base (NaOH)
There are Strong base and Weak
base types of resin
Separate/Single Bed Deionizer
Separate columns for cation and anion
exchange resin
Single regenerant chemical for each
column
Simple regeneration process-no resin
separation or mixing
Separate Bed Deionizer
Effluent quality normally in range of 1
to 10 ppm TDS using co-current
regeneration
Effluent quality normally in range of
0.1 to 1 ppm TDS using counter-
current regeneration
Separate Bed Deionizer
Effluent resistivity range is normally
0.05 to 0.5 megohm-cm using co-current
regeneration
Effluent resistivity range is normally
0.05 to 10 megohm-cm using counter-
current regeneration
Separate Bed Deionizer
pH difficult to predict
- wide range (3-11)
- can shift from alkaline to acidic during
run
Operation is generally simple and
reliable
Mixed Bed Deionizer
Sigle cation/anion resin column
Complex regeneration procedure
requiring resin separation and mixing
Effluent quality normally in range of 0 to
0.5 ppm TDS
Mixed Bed Deionizer
Effluent resistivity normally 1 to 18.3
megohm-cm
Product pH normally 6.8 to 7.2
Operation is generally reliable but is
morn difficult than separate bed
deionizer
Mixed Bed Regeneration Cycle
Backwash for rasin separation
Chemical introduction
Slow rinse
Fast rinse
Blow down
Air mix
Final rinse
Chemical Regeneration Requirement
Proper chemical strength
Proper chemical dosage
Proper chemical contact time
Proper chemical flow rate
Hot caustic for best silica removal
Off-Site Regenerated Deionizers
(exchange barrels)
Lower capital cost (or lease)
Higher operating costs
Easily expanded
Less control over quality
No chemical handling
Non-Regenerable New Resin
Deionizers (throw-away)
Highest operating cost
Highest quality control
Minimal TOC elution with proper resin
Resin supplier batch Q.C. documentation
should be available
Often used in small lab systems
Hot Water Sanitizable Deionizers
To help manage bio-burden
Electropolished 316 L SS vessels
Sanitary piping connections
Match loop construction quality
Sanitize at 65-80
o
C
Ion Exchange Resin Pretreatment
Multimedia Filter-Suspended Solids Removal
Cartridge Filter- Suspended Solids Removal
Activated Carboon Filter-Chlorine Removal,
Organic Reduction
Sodium Bisulfite Injection Chlorine Removal
Greensand Filter Iron Removal
Organic Scavenger Organic Reduction
Ultraviolet Steriliser Bacteria Reduction
Ion Exchange Resin Bacteria
Control Methods
Frequent chemical regeneration
Standby recirculation
Hot water sanitization
Chemical sanitization
- Peracetic acid
- Chlorine
- Formaldehyde
- Hydrogen Peroxide
Replacement
VII. Purified Water System Design
Purified Water Quality Requirements
Conductivity : e.g. USP 3 stage
measurement procedure
Total Organic Carbon: 500 ppb limit
response
Microbial Action Limit: 100 cfu/ml
maximum
- may be lower for process and product
specific applications
System Design Parameters
Meet Current Industry Standards (e.g. EP,
USP, FDA, GMP, GAMP, etc.)
Product meets USP Standards for Purified
Water at system outlet (i.e. no loop polishing
allowed)
Systems continuously recirculate in standby
mode
Some of the most common process
configurations
System Selection Considerations
Microbial Control
Capital Equipment Cost
Operating Cost
Lifecycle Cost
Chemical Handling
Reliability / Uptime
Maintenance
Water Consumption / Discharge
Footprint plantroom space
Consistent TOC Limit Attainment
Consistent Conductivity Attainment
Entrance for water system
Pump for water system
Control system for Purified water system
Reverse osmosis system for purified water
Mixed bed for residue resins
Storage for purified water with ozone
VIII. Water for Injection/s production
Techniques
Water for injection
USP-Prepared from water meeting the EPA
NPDWR or comparable regulations for Potable
water
Contains no added substance
Same chemical requirements as Purified Water
with added endotoxin specification (<0.25EU/ml)
Accepted microbial limit <10 cfu/100 ml
Water for injection
USP-Prepared by Reverse Osmosis or Distillation
(terminal process)
Japanese Pharmacopoeia allows ultra-filtration as
final process
EP, EU Pharmacopoeia allows only distillation
Distillation
Preferred method of production for WFI
Purifies water by phase change and entrapment
separation
Removes :
ionic contaminants
non-volatile organics
microorganisms
endotoxins
Distillator
Control panel for distillator
Storage with heater (>80c) for water for Injection
Other Design Considerations
Capital Equipment Cost
Operating Cost
Life cycle Cost
Chemical Handling
Reliability / Uptime
Maintenance
Water Consumption / Discharge
Utility Requirements
Space Limitations
IX. Reverse Osmosis Basics
Reverse Osmosis
Pressure driven semi-permeable membrane
process
Implemented for reduction of :
Inorganic contaminants
Organic contaminants
Colloids
Microorganisms
Endotoxins
Reverse Osmosis
Performance measurement/determination
Salt rejection
Comparative conductivity (product to
feed)
Microbial reduction
Endotoxin reduction
Cross Flow Comparison
Microfiltration
Ultrafiltration
Nanofiltration
Reverse Osmosis
10.0
Micron
1.0
Micron
0.1
Micron
0.01
Micron
0.001
Micron
0.0001
Micron
Spiral Wound RO Module
Reverse Osmosis
Microbial concerns
Most systems cannot tolerate chlorine in
feed water at it tends to hydrolyse the
membranes
Significant bio-film and planktonic counts
can occur
Frequent sanitization is often required
Pretreatment system performance is
significant factor
Preventing Biological Fouling
Utilize proper membranes
Sound sanitization plan
Minimize incoming challenge
Feed disinfectant (Cl
2
, O3, etc.)
HWS Carbon Filters
Ultraviolet Lights to reduce challenge
Lower unit recovery targets
Reverse Osmosis Sanitization
Peracetic acid
Sodium hydroxide
Formaldehyde
Hydrochloric acid
Hot water 80
0
C
RO Specification
Pretreatment and post-treatment
Feed filter housing (and elements)
Chemical tanks / pumps / controls
Cleaning skid (or sanitization skid)
RO Pretreatment Parameters
Feed water quality
Membrane type
Product water quality specifications
Two Pass Reverse Osmosis
Two RO units in series (product stream)
Known as two pass
Capable of producing USP 28/EP Purified
Water
USP 28
Generally Stage 2 or 3 conductivity
Sometimes meets Stage 1 limit
Excellent TOC reduction
Two Pass Reverse Osmosis
Excellent endotoxin reduction
Excellent microbial reduction
Can produce WFI when properly designed
and maintained
Sanitary construction
Continuous recirculation
Frequent hot water sanitization
Proper pretreatment
Typical Two-Pass RO System
Reverse Osmosis for WFI
Disadvantages :
Membrane integrity
Bacteria grow-through
Seal leakage or bypass
Chemical attack
High temperature damage
Difficult to integrity test
Reverse Osmosis for WFI
Disadvantages :
Sanitization limitations
Temperature limit
Chemical resistance
Pretreatment cost may be high
Reverse Osmosis for WFI
Advantages :
May be substantially lower in capital cost
than stills
May have substantially lower operating
costs than distillation
X. Storage and distribution
System Installation Considerations
Basic Approaches are :-
Store hot draw-off hot.
Store hot draw-off cold.
Store cold draw-off cold sanitise thermally
Store cold draw-off cold sanitise chemically
(ozone or other chemicals)
These techniques can be applied to both PW,
WHP & WFI.
Distribution General Considerations
Maintain water quality within acceptable limits
Limited water quality degradation is
acceptable degradation below quality limits
is not
Deliver water to use points at required flow,
pressure and temperature
Distribution General Considerations
Minimize capital and operating costs
Minimize time water is held at conditions
which favor microbial growth
Minimize temperature changes
Contact all areas during any sanitisation cycle
Distribution General Considerations
Batch operation
Utilizes at least two storage tanks
One is in service to users while other is
filled/tested
Filled tank enters service after successful
testing
Water usually sanitized before refill
Tank usually sanitized before refill
Batch System Operation Advantages
Water is tested before use
Each batch has QA/QC lot release
Maximum traceability and identification
Batch System Operation Disadvantages
Cumbersome to operate
Usually limited to small systems
High capital costs
High operating costs
Traditionally used to overcome unreliable
means of water production
Distribution Design Concepts
Dynamic/continuous operation
Off-sets peak demand with continuous make-
up into single tank
System supplies users continuously while
maintaining quality
Dynamic Continuous System
Advantages
Lower life cycle costs
Less complex piping at tanks
Disadvantage
No individual lot traceability for water
Distribution System Critical
Parameters
Water quality requirement
QA release required before use
Continuous recirculation requirements
Limiting hydraulics
Hot users only
Low temperature users only
Distribution System Critical
Parameters
Number of total low temperature users
Hot storage desired
Energy consumption critical
Sanitization method
Pressure requirements
Future considerations
Distribution System Critical
Parameters
Use loop filters NO ! can hide systemic
contamination problems
Use point filters NO !
Cost constraints
Available feed
Feed water quality
Feed interruptions
Reserve capacity production issues
Different Criteria Lead to Different
Designs
Batched tank recirculating system
Parallel loops, single tank
Hot storage, hot distribution
Hot storage, hot distribution, with point of use
heat exchanger
Different Criteria Lead to Different
Designs
Hot storage, cool and reheat
Hot storage, self-contained distribution
Ambient storage, ambient distribution
Ozonated storage and distribution
Pass thru system
System Comparison Parameters
Capital cost
Water consumption
Energy consumption
Ease of validation
Ease of operability
Maintenance requirements
System Comparison Measures
Tank turnover
Distribution system water content filling the
system must be considered
Line flushing requirements
Ability to respond to large peak demands
Loop balancing and control requiremetns
Microbial/endotoxin growth potential
Materials of Construction
Comparison Factors
Corrosion resistance
Availability
Extractables
Degree of Thermal expansion
External support requirements
Joining method
Storage and Distribution Sanitization
Periodic sanitization generally required
After maintenance in hot systems
Routine in ambient temperature systems
Frequency should be established through
monitoring
Response to reaching action level
Consider frequency in system annual review
Sanitization Options
Clean Steam
Extremely effective & verifiable
Requires full drainability & venting
Beat in SS
Possible in PVDF
Requires continuous support
Requires significant expansion loops
Limited to 140
0
C
Sanitization Options
Hot water
Very effective at 80
0
C
Can be done under pressure >100
0
C
Best in SS
Easily verified
Easily automated
Sanitization Options
Ozone
Best in SS and PVDF (+PP)
Very effective if frequent enough
Easily automated if already continuous in
storage tank
Easily removed with UV
Verifiable with monitors
Difficult to sanitize through use point valves
Good at biofilm removal with time
Sanitization Options - Chemical
Peracetic acid
Sodium hydroxide
Hydrogen peroxide
Quaternary ammonium compounds
Most difficult to verify
Most difficult to automate
Most difficult to rinse
Compatible with wide range of materials
XI. Ozone Biocontamination Control
Ozone
Allotrope of oxygen three atoms, 0
3
Relatively unstable
Half-life varies-10 to 120 minutes
Solubility about 13 O
2
OSHA atmosphere limit= 0.1 ppm
Potentially explosive at O
3
/O
2
mixtures>20%
- this cannot occur in water
Ozone
Microorganism kill faster than chlorine
Most bacteria killed in seconds
Lyses cell wall-not dependent on diffusion
through cell wall
8-12 minute kill for spores and Giardia
cysts
Ozone
Capable of organic oxidation including
endotoxin
Easily removed by ultraviolet light
- low pressure 254 nm or medium
pressure (multiple wavelength)
- requires about 3 the germicidal dose
Compatible with SS and PVDF
Electrolytic Ozone Generation
The preferred method for Pharma
Electrolytic generator
- Uses deionized water as feed
- Generation from water eases mixing
problem
- Electrolysis of water at anode yields
oxygen and ozone
- Lead (IV) oxide anode catalyst for O
3
- Hydrogen produced at cathode
Electrolytic Ozone Generator
Minimal ionic contamination
No danger of atmospheric O
3
release
Lower ozone levels effective (better
mixing)
Higher capital cost offsets lower O
3
level advantage
Direct current (DC), which is fed to the cell,
splits the passing de- mineralised water
into ozone, oxygen and protons on the
anode side and hydrogen gas is
produced on the cathode side.
The ozone generation takes place in a by-pass
stream off the pure water loop. The
ozone, which is dissolved in the passing
water, is distributed from the by-pass
stream back into the pure water loop
and the storage tanks.
Advantages of a ozone generator
system
No contamination by ions as the ozone is directly
produced from and dissolved in demineralised
water
Effective microbial reduction, TOC and endotoxin
decomposition at low ozone concentrations in pure
water
Continuous operation without additional
periodical disinfection with chemicals or steam
Easy installation and commissioning, low
maintenance and operating costs
Ozone Removal
Dissolved
- Ultraviolet light (3germicidal dose)
- Activated carbon
- Heat
- Time
Gas
- Manganese dioxide catalytic device
- Heat
Ozone Measurement
Chemical testing
- Indigo tri- sulfonate solution
decolorization
- absorbance change of 600 nm light
- linear with ozone level
- preferred method
- Potassium iodide color change
- interference from oxidants
- less preferred
Ozone Measurement On-line
Electrolytic membrane amperometer
- electrochemically converts ozone to
oxygen
- measures current required for
conversion- proportional to O
3
- good sensitivity
- membrane minimizes electrode
fouling and oxidant interference
Industry Views on Ozone
Many successful ozonated systems
Many FDA audits of several
systems
have been successful
Regional trends are variable about
use of ozone
Industry Views on Ozone
Not necessarily as effective as
maintaining a system at 80
o
C-but close
Much better than no heat or no Ozone
Ozone better a destroying bio- films
Some use heat sanitization for use points
Ozone Issues
Removal prior to use
Product efficacy impacted by trace
levels?
Personnel Safety monitoring required
During service periods the UV unit is in
operation, so only the storage tank and
the distribution system are Ozonated.
In most ozone applications the UV unit is
switched off during down periods. so that
the water containing ozone disinfects the
entire distribution system.
The residual ozone and proof of ozone
decomposition is monitored with
calibrated electrochemical on- line
sensors.
XII. System Materials and
Finishes Considerations
Piping Systems
Material
- Stainless Steel 316 L.
- Seemless or drawn tube may be used.
- Tube mill finished 2B internally + mechanically polished
as part of tube manufacturing process.
- Electropolish improves finish and surface corrosion
resistance.
Insulation
- Pipework insulated with chloride free materrials. In
process areas, Insulation needs to be hygienic finish
Drainability if required
- Valve configuration
- Slope
MATERIALS SELECTION S
Corrosion minimisation and resistance
Avoidance of leachates from contact
materials
Avoidance of the development and
adherennce of bio-films
Avoidance of adhesion and retention of
contaminants and cleaning/disinfecting
residues
Aesthetically appropriate appearance
Inspectability of surfaces
Ability to joint materials
Tube and Fittings Materials of
Construction
Product contact
- 300 series SS (304,304L, 316, 316L)
- Hastelloy
- AL 6XN
- Monel, titanium, Inconel etc.
AUSTENITIC STAINLESS STEEL
COMPOSITION
Composition % 304 316L
Carbon (max) 0.08 0.03
Chromium 18.5 17.0
Nickel 9.5 13.0
Molybdenum 0 2.25
Piping system
PLASTICS PIPELINE MATERIALS
PEEK Poly-ether-etherketone
PVDF Polyvinylidenedifluoride
PFA Perfluoroalkoxy
PP Polypropylene
ABS Acrylonitrile-butadiene styrene
PVC Polyvinyl chloride
- peek>20Xcost of PVC
- main value in Microelectronics
Common Specification for non-
compendial Ultra-pure Water
This specification now being demanded
for critical analytical tasks where trace
contaminants may obscure the test
targets
Inorganics 10-15 megOhm-cm
Organics < 50 ppb TOC
Particulate < 0.2
Bacteria < 10 cfu/ml
PLASTICS PIPELINE MATERIALS
for non-compendial Ultra-pure Water
PVDF Polyvinylidenedifluoride
PP Polypropylene
The following will not satisfy the
likely microbiological control limits
ABS Acrylonitrile-butadiene-
styrene
PVC Polyvinyl chloride
EXAMPLES OF APPROVED
CONTACT MATERIALS
Pure gum rubber
Black butyl rubber
Teflon PTFE
EPDM
Buna N
White butyl rubber
Silicon rubber
Surface Finishes applied to
Stainless Steel
BS Finish
reference
Typical Ra

m
General Description
0
1
n/8
5.0
Hot roll, softened, not descaled
Hot roll, soffened, descaled
2D 0.5 Cold roll, softened, descaled
2B 0.275 Cold roll, softened, descaled,+
Roll on pollshed rollers
2A 0.088 Bright annealed
3A 1.5 Ground Brush,
4 0.8 Polished with fine grit
8 - Mirror polish
SURFACE FINISH
THE EFFECT OF ELECTROPOLISHING
A highly reflective finish can be obtained with
an R
a
Value < 0.02m
Starting surface is critical to quality achieved be
electropolishing. 2A or 2B cold rolled is
appropriate.
Used to be an essential specification in the dairy
industry. Now not so frequent as CIP Systems
and Chemicals improve.
Electropolishing diminishes the passive layer.
This must be restored to retain corrosion
resistance.
Installation QA Tasks
Materials certificated from supplier
Materials and equipment controlled at job site
Documented
Clean
In correct condition e.g. clean & dry
plant items.
Dispensed for installation.
Clean Installation protocol
Installation QA Tasks
Weld Log
Operator
Qualification
Checks/Certification
Equipment
Reference
Settings
Maintenance
Samples
Weld i/d
Installation QA Tasks
Installation Records
Specifications
Drawings
Components
Change control records
Installation QA Tasks
Inspection
Visual - Boroscope
Photograph
Samples
X-ray
Retained Samples
XIII. Commissioning and Validation
Commissioning Overview
Take equipment from installation to
operation
Incorporate a systematic method of testing
and documentation
Proper commissioning tests and
documentation satisfy many IQ/OQ
requirements
Differences between Commissioning
and Validation (1)
Commissioning Supplier
Responsibility
Validation User
Responsibility
Objective is to identify and
rectify problems
Demonstrate process is
as specified and under
control
Approved protocol not
required; link to validation
Must follow an
approved protocol
Typically operated by
supplier
Owned & operated by
user
Differences between Commissioning
and Validation (2)
Commissioning Validation
Not all data and
adjustments are
recorded & reviewed
All data & adjustments
must be
recorded/reviewed
No written report unless
specified
Written report is required
Reviewed for acceptance
by engineering/project
team
Reviewed and approved
by Quality Assurance
Commissioning Documents (1)
Generated by team
Vendors
Engineering firm
Construction contractors
Owner
GEP requirements
Timely Accessible
Witnessed Authorised
Commissioning Documents (2)
Lists :
Equipment (id; manufacturer; model.)
Piping (segment id; type; size & finish)
Valves (id; location; type size & finish)
Instruments (id; location; type , purpose,
critical/non-critical, range & calibration date)
Controllers and alarms
Filters (id; location; type; size; construction;
manufacturer; model & pore size)
Commissioning Documents (3)
Lists :
Process & utility connections.
System name
Supply pressure
Flow rate
Temperature
Electrical requirements
Materials of construction for product contact
Spare parts
SOPs (operation, maintenance, calibration,
monitoring)
Commissioning Documents (4)
Factory Testing Documents :
Equipment test procedures
Pressure tests
Safety checks
Calibration procedures & data sheets
PLC/PC testing
Sequence of operation testing
Commissioning Documents (5)
Weld Documentation :
Weld isometrics
Welder certification/qualification
Equipment certification
Weld inspection (logs, tapes, coupon id and
storage records)
Weld Procedures
Commissioning Documents (6)
Calibration Documentation :
Critical/non-critical instrument list
Critical instruments must be calibrated via
traceable methods before OQ
Non-critical instruments typically calibrated
prior to OQ
Calibration frequency of critical and non-
critical instruments may vary
Standard Operating Procedures
Should be drafted early as possible
Should include :
start-up/shut-down (normal/emergency)
sanitisation/cleaning
operation (including log)
sampling/testing
specific procedures
chemical addition, etc.
Commissioning Requirements (1)
Prepare equipment for operation
Start and verify operation of each component
Verify whole system
Use draft SOPs for start-up
Establish operation log
Commissioning Requirements (2)
Record actual system parameters and ranges
Perform statistical review if possible
Establish alert levels
Establish action levels
Review system readiness for balance of
OQ/PQ testing
Validation Overview
System Design (pre-validation)
Installation Qualification
Operational Qualification
Performance Qualification
Change Control
Regular Review (Annual system review)
This presentation will not deal with all the
normal validation steps. BUT PQ is special for
water systems

(Installation Qualification for Purified Water)

1.
1.1 Non-Return (Foot Valve)
1.2 Lowara CA200/35 3 2
1.3 UPVC 1
1.4 Non-Return
1.5 Power Supply 3 PH/ 380 V/ 50 Hz
2. 200
2.1 1
2.2 1
2.3
2.4
2.5 100
3. Ametek 20 /30
2
3.1 3/4
3.2 3/4
4. 38x120 .
4.1 Multiport Autotrol 180/450
4.2 1
4.3 1
4.4
4.5 POWER SUPPLY 220 V
4.6 SAMPLING VALVE
5. S 37B
5.1 1
5.2 1
5.3 POWER SUPPLY 220 V
5.4 UV-MONITOR
-
-
6. REVERSE OSMOSIS 1500 L/Hr
6.1 1
6.2 3/4
6.3
6.4 ANTISCSLE / PE 100 / Chemical Pump
6.5 Power Supple 3 PH / 380 V / 50 Hz
6.6 VERTICAL MULTISTAGE PUMP 4
6.7 VESSEL FIBERGLASS 3 SETS + MEMBRANE 6 SETS
6.8 PRODUCT FLOWMETER
6.9 CONCENTRATE FLOWMETER
6.10 RECYCLE FLOWMETER
6.11 Controller ROF 900E
7. RO. 3,000
7.1 1 /
7.2 1 /
7.3 Manhole 18
7.4 VENT FILTER
8. 4HMS5 0.75 Mixed Bed 2

8.1 1
8.2 1
8.3 POWER SUPPLY 1 PH / 220 V / 50 Hz
8.4 Non-Return Valve
9. 38x185 .
9.1 - 1
9.2 PLASTIC DIAPHRAGM VAVE 1 8 / 1/2 6
9.3 STAGER CONTROLLER 1
9.4 AIR COMPRESSOR 1
9.5 SIGHT GLASS 2
9.6 1
9.7 SAMPLING VALVE
9.8 NaOH 50% TANK (PE)
9.9 EJECTOR () NaOH
9.10 HCI 35% TANK (PE)
9.11 EJECTOR () HCI
9.12 2,500
9.12.1 CHEMICAL PUMP Prominent ConB 1601 PP1
9.12.2 INLET / OUTLET
9.12.3 CHEMICAL PUMP Prominent ConB 1601 PP1
9.12.4 INLET / OUTLET
9.13 PH CONTROLLER HANNA HI981411-1
9.14 Lowara DOMO7 0.75
9.15 1
9.16 1
10. 20 / 5 1 / 1 1
10.1 1
10.2 1
11. LM-1
11.1 POWER SUPPLY 220 V 50 Hz
11.2 ELECTRODE SO-1 C=0.1
12. Sanitron S 50B
12.1 1 1/2
12.2 1 1/2
12.3 POWER SUPPLY 220 V
12.4 UV-MONITOR
-
-
13. 6,000
13.1 1 1/2 / 1 1/2
13.2 /
13.3 Solenoid Valve
13.4 Manhole 18
13.5 VENT FILTER
14. 2 INOXPA EFI 2340
14.1 1 1/2 (Sanitary Type)
14.2 1 (Sanitary Yype)
14.3 Non-Return Valve
14.4 POWER SUPPLY 3 Phase/380 V/50 Hz
14.5
15. 3 1 / 0.45 / 0.2
15.1 100
15.2 1
15.3 1
16. Sanitron S 50B
16.1 1 1/2
16.2 1 1/2
16.3 POWER SUPPLY 220 V
16.4 UV-MONITOR
-
-
17. CD 15/AD 4.5 /
17.1 AIR FLOW METER
17.2
17.3
17.4 INJECTOR MANIFOLD
17.5 STATIC MIXER
17.6
17.7 POWER SUPPLY 220 V / 50 Hz / 1.52 A
18. 1,500
18.1 1 / 1
18.2 /
18.3 Manhole 18
18.4 VENT FILTER
19. 2 INOXPA EFI 2340
19.1 1 1/2 (Sanitary Type)
19.2 1 (Sanitary Yype)
19.3 Non-Return Valve
19.4 POWER SUPPLY 3 Phase/380 V/50 Hz
19.5
20. 3 1 / 0.45 / 0.2
20.1 100
20.2 1
20.3 1
21. Sanitron S 37B
21.1 1
21.2 1
21.3 POWER SUPPLY 220 V
21.4 UV-MONITOR
-
-
22. M 15/AD 2.8 /
22.1 AIR FLOW METER
22.2
22.3
22.4 INJECTOR MANIFOLD
22.5 STATIC MIXER
22.6
22.7 POWER SUPPLY 220 V / 50 Hz / 1.52 A
23. 316L ( TEST )
Operation Qualification Purified Water
1. (1.1) 2 1 ..
2. 40 80 PSI ..
3. 30 (1.2) ..
4. Activated Carbon (1.3)
- Backwash ..
- Backwash ..
5. (1.4)
..
6. REVERSE OSMOSIS (1.5)
- Anti-Scale Feed 1 ..
- Inlet Pressure > 20 PSI Pre-Filter ..
- Low Pressure Switch
High Pressure Switch ..
- Pressure Drop Pre-Filter RO < 5 PSI ..
- Pressure Pre-Filter > 20 PSI ..
- Membrane Pressure 130 250 PSI ..
- Product > 1,500 ..
- > 500 ..
- Circulate > 1,000 ..
- Automatic Flushing 24 ..
Flush
- Flush 3 ..
- Test Flush Conductivity ..
- Flush
..
- Conductivity
20 ....
- Concentrate ..
- Solenoid UV (1.4)
RO ..
7. (1.6) , (1.19) (1.12)
- ..
- ..
- ..
8. (17.) , (1.20) (1.12)
1 ..
9. Mixed Bed Stager
- Step Stager ..
- HCI (35%) ..
- NaOH (25%) ..
- Air Compresser ..
-
1 ..
- Test Solenoik Valve ..
Mixed Bed (1.8) Filter (1.9)
Conductivity Meter

( Conductivity 1 )
10. (1.11) , (1.17) ..
(1.24)

11. Test Ozone (1.25) , (1.18) ..

- Test Injector
() ..
12. Loop
2 Bars ..

Pressure Tank
(1.1) ( )
Activated Carbon
(Cl
2
) (ppm.) ---> ( 0.1 ppm.)
RO Pre-Filter (1.2)
Filter RO RO
Pre-Filter Membrane Flow (L/Hr)
Product Concentrate Circulate
Conductivity
(Microsiemens)

O3 (ppm)
pH value
TOC (ppb)
(CFU/ml)
Conductivity ()/
0
C
4 3 2 1 ................

(Installation Qualification for Water for Injection)

1. 500
1.1
1.2 FEED GRUNFOS CRN2-70
1.3
1.4 SENSOR
1.4.1 SENSOR , CONDUCTIVITY Loop 1
1.4.2 SENSOR 1
1.4.3 SENSOR , CONDUCTIVITY Loop 2
1.4.4 SENSOR 2
1.4.5 LEVEL SENSOR 1
1.4.6 LEVEL SENSOR 2
1.4.7 DI (1.12)
1.5 CONTROL PANEL
1.6
2. 4,000 (2.4)
2.1 6 KW 2
2.2 2 HP /3 PHASE
2.3 VENT FILTER
2.4 LEVEL PROBE
2.5 CIRCULATE
1 Self drain Dead leg Diaphragm
3. 1,500
3.1 6 KW 1
3.2 2 HP/3 PHASE
3.3 VENT FILTER
3.4 LEVEL PROBE
3.5 CIRCULATE
1 Self drain Dead leg Diaphragm
4. COOLING TOWER 40
4.1 1
4.2 380 V/50 Hz
4.3 PUMP CIRCULATE COOLING 380 V / 50 Hz
4.4 CIRCULATE COOLING
CONDENSOR BY-PASS VALVE
5. DRAIN ,
6. STEAM BOILER
6.1 FEED
6.2 FEED Anti-Corrosion
6.3 500 Kg / Hr
6.3.1 3
6.3.2 VENT VALVE
6.3.3 SAFETY VALVE
6.3.4 DRAIN
6.3.5 PRESSURE GAUGE 200 PSI
6.4 HEADER
6.4.1 SAFETY VALVE
6.4.2 PRESSURE GAUGE 200 PSI
6.4.3 STEAM TRAP
6.5 500
6.5.1
6.6
6.7 380 V / 50 Hz / 3 PH
7. STEAM
Operation Qualification Water For Injection
1. Boiler (2.2)
- Pressure 3-6 Bars .
- .
- .
2. (2.2)
- Feed .
- 80-98 .
- Conductivity < 1 .
- > 500 .
- 2 .
- Probe .
- Probe Loop 1 .
- Probe Loop 2 .
- Probe Conductivity
Loop 1 .
- Probe Conductivity
Loop 2 .
- Probe Loop 1 .
- Probe Loop 2 .
- Heated Vent (2.4) .
- Filter 100-120 .
- Heated Vent (2.7) .
- Filter 100-110 .
- Test Heater (2.4) .
- Test Heater (2.7) .
- Test 2.5 2.8
Loop 1 2 Bars Bars
- Cooing Tower
Condensor .
- Cooling Tower .
- Steam Generator
1) 1 Bar .
2) 3 Bars .
Water for Injection System Records
- ................................
- Conductivity < 1
- 100 CFU/ml
- TOC (ppb) at
0
C
- SIP ....................

................ 1 2 3 4
Conductivity ()
(CFU/ml)
TOC (ppb)
pH value
Performance Qualification
Activity expected by Regulator (but perform
for Company!)
Documented verification of proper system
operation in meeting predetermined
acceptance criteria
Follows IQ and OQ execution and resolution
of all critical deviations
Documentation Required to Write PQ
P & ID
User Requirement Specification
Pertinent regulations, guidelines and owner
specifications
Proven SOPs in place
PQ Sampling Program Objectives
Phase 1-- typical duration 2-4 weeks
Develop appropriate operating ranges
Develop and finalise operating, cleaning and
maintenance procedures
Demonstrate production and delivery of
product water of the required quality
PQ Sampling Program Objectives --
Phase 1 (Slide 1)
Sample after each step in treatment process
Sample at each point of use
Sample incoming feed water -- verify feed
water quality
FDA Water Guide suggests daily sampling --
alternate may be acceptable
PQ Sampling Program Objectives --
Phase 1 (Slide 2)
Chemistry testing specific to unit process
Microbiological testing for each unit process
At completion SOPs for operation,
maintenance and trouble shooting finalised
PQ Sampling Program Objectives --
Phase 1 (Slide 3)
Alarm response/action levels verified
Test failure process developed
Is failure localised? (specific port)
Define handling of different failure types
PQ Sampling Program Objectives
Phase 2
Typical duration 2-4 weeks
Demonstrate consistent operation within
established ranges
Demonstrate consistent production and
delivery of water of the required quality when
system operated to SOPs
Sampling scheme / duration same as Phase 1
PQ Sampling Program Objectives
Phase 3
Typical duration one year
Demonstrate extended performance
Ensure that potential seasonal variations are
evaluated and treated
Sample locations, frequencies and tests based
on established procedures
Change Control (1)
Assess potential impact of change
Determine required actions testing,
documentation changes and conditions for use
Provide audit trail for changes, testing and
approval
Change Control (2)
During design and construction -- GEP
During commissioning/validation -- eliminate
unnecessary signatures
Post-validation minor changes
use ongoing data
use Quality Assurance Assessment
Revalidation
Appropriate for major system changes
Determined via change control process
Periodic revalidation is not required
Perform regular review
Validation Summary (1)
Integrated approach
Document hierarchy clarifies document
purpose/relationship
Effective commissioning satisfies many
validation test requirements
Prepares the way for effective maintenance
and trouble shooting
Validation Summary (2)
Sampling program tailored to particular system
Change control methods may change during
project life cycle
Periodic revalidation not required
V-Model
User Requirement
(i.e. What)
Performance
Qualification
PQ Test Plan
Functional Design
(i.e. How as Schematic)
Operational
Qualification
OQ Test Plan
Design
Development
Detail Design
(i.e. How to make)
IQ Test
Installation
Qualification
Impact Assessment
Implementation
XIV. System Maintenance and
Troubleshooting
A natural progression from System Design &
Validation
Good design/validation
+ defined maintenance
= Few troubles
Need Troubleshooting strategy
System Maintenance and
Troubleshooting
No sytem 100 % reliable
Expect occasional quality problems
and mechanical failures
Plan a controlled response to the
unexpected
System for Troubleshooting
Know and understand your sytem
Consider Maintenance and
Troubleshooting at design/validation
stage
Develop standard approach to
Troubleshooting
Follow plan, avoid panic or short cuts
Know Your System
Understand contribution and operation of
each component and system parameters
How it works
Normal parameters
Sensitivity to change
Maintenance requirements
Troubleshooting Procedure
Methodical, no panic
Collect evidence
samples
Instrument readings
Compare with reference (validation) values
Identify source of problem
Take remedial action
Review, document, learning
Importance of Monitoring
Maintain product quality
Maintain equipment
Protect investment
Detect changes in incoming water
Maximise run time
Minimise service time
Historical tracking
Stringent Change Control
Factors to Consider (1)
Feed water quality
Change in supply
Sudden variations
Temperature
Seasonal
Adverse weather (floods, drought)
Monitor and trend quality of feed water
quarterly
Feed Water Parameters
Total dissolved solids (conductivity)
pH
Chlorine
Density index
Total Organic Carbon
Site specific contaminants silica, iron
Factors to Consider (2)
Final product water quality & quantily
Chemical attributes
Microbiological profile
Endotoxin content
Volume produced
Perform trending and address trends early
(Detailed monitoring programme, monthly
trending, annual review)
Final Water Quality/Quantity
Parameters
Flow rate
Conductivity
TOC
Microbial Count
Endotoxin level
Specific contaminants
Factors to Consider (3)
Equipment Considerations
Unit process
(ie individual component performance)
Maintenance history
Change Control
Parts
Feed water changes
Product water changes
Unit Process Monitoring
General Considerations
Understand individual components
Document current setting/ readings
Compare with original (validated)
Check maintenance requirements met
Review documented changes
Purified Water System validation
- Pressure Tank ..................................
- Pre-Filter (1.2) ..........................
- Pre-Filter RO System ..........................
- Membrane RO System .......................
- Reverse Osmosis > 1,500 /
Conductivity 20
- Deionizer Mixed Bed Conductivity
Dei 1 2 1
- Deionizer Mixed Bed .3,000 /
- Filter 1.21, 1.22, 1.23, 1.14, 1.15 1.16 .......................
- Dei Circulate Loop Conductivity < 1
............
- CIP 100 CFU/ml ..................
- TOC < 500 ppb.

1)
400C
2) PRESSIRE GAUGE
() PRESSURE GAUGE
30-60 PSI () DRAIN
()
3)

6
4) ACTIVATED CARBON

(BACK WASH)

5) UV-MONITOR
0.4-10 () 0.4 ()
UV
QUARZT (WIPER) 2-3 DRAIN
DRAIN
6) REVERSE OSMOSIS PLC
AUTO FLUSHING FLUSH CONDU CTIVITY
FLUSH FLOW METER PRESSURE GAUGE

7) MIXED BED RESIN
(REGENERATE) 1 1
-


8) -
- -

-
- Carbon Filter
- Ozone, Conductivity DI

- Conductivity Mixed bed

- UV UV
- RO Pre-Filter Membrane
Product,
Circulate
- - Mixed Bed
-
-
- Anti-Scale Anti-Scale RO
-
NOTE : - Carbon Filter .......... ppm.
- ............ ppm.
- Conductivity Mixed Bed 1

- UV

-
References:
1) FDA,Guide to inspection of High Purity Water System July 1993
2) ISPE Baseline Pharmaceutical Engineering Guide, and Water and
Steam System
3) ISPE Baseline Pharmaceutical Water System
4) USP 28: 2005
5) BP 2002 ,Volume 1 and 2
6) Ph.Eur 4
th
,Edition
7) Gordon Farquharson: Pharmaceutical Grade Water Basis
8) Robert Chew : Commissioning and Qualification of Water
9) Antony Margetts: Validation Concept