validation of water system
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A Seminar On
VALIDATION OF WATER
SYSTEMS FORPHARMACEUTICAL USE
Prepared By: Vinay B. Patel
Harshal Thakkar
DEPARTMENT OF QUALITY ASSURANCE
SHRI SARVAJANIK PHARMACY COLLEGE
MEHSANA, GUJARAT
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Introduction Water is the most widely used substance, raw material
or starting material in the production, processing andformulation of pharmaceutical products.
It has unique chemical properties due to its polarity and
hydrogen bonds. This means it is able to dissolve,
absorb, adsorb or suspend many different compounds.
These include contaminants that may represent hazards
in themselves or that may be able to react with intended
product substances, resulting in hazards to health.
Different grades of water quality are required depending
on the route of administration of the pharmaceutical
products.9/20/2013 2
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Principles
Like any starting material, water must conform to Good
Manufacturing Practice norms
It must be potable and comply with WHO Guidelines
for drinking-water quality
Potential for microbial growth
Systems must be properly validated
Water for parenteral use could not be contaminated with
pyrogens or endotoxins
Specifications and periodic testing is required9/20/2013 3
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Types of water
1. Purified water
2. Water for Injections PFW & WFI
3. Softened Water
4. Water for Final Rinse
5. Pure, or clean Steam
6. Water for cooling Autoclaves
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Why purify raw water?1. Although reasonably pure, it is always variable
2. Seasonal variations may occur in water
3. Some regions have very poor quality water
4. Must remove impurities to prevent product
contamination.
5. Control microbes to avoid contaminating products
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Contaminants of water There is no pure water in nature, as it can contain
up to 90 possible unacceptable contaminants
Contaminant groups:
1. Inorganic compounds
2. Organic compounds
3. Solids
4. Gases
5. Micro-organisms9/20/2013 6
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Problem Minerals
1. Calcium and magnesium
2. Iron and manganese
3. Silicates
4. Carbon dioxide
5. Hydrogen sulfide
6. Phosphates
7. Copper
8. Aluminium
9. Heavy metals ( Arsenic, lead, cadmium)
10.Nitrates
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Micro OrganismsBiofilm
1. Algae2. Protozoa
Cryptosporidium
Giardia
3. Bacteria
Pseudomonas
Gram negative, non-fermenting bacteria
Escherichia coli and coliforms9/20/2013 8
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Turbidity1. Silt, clay, and suspended material cause turbidity
2. Small particles include "colloids"
3. Removal of colloids is usually the first step in water
treatment
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Water hardnessWater hardness classification mg/L or ppm as CaCO3
Soft 0-60
Moderate 61-120
Hard 121-180
Very Hard > 180
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Source of raw water1. Rain water
2. Surface or ground water
3. Well or borehole
4. Municipal or civiltap water
5. Purchased in bulk
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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
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WHO water treatment guidanceThe following should be monitored
Sources of water
Treatment procedures
Water treatment equipment
Treated water tests Monitoring records required
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Pre-treatment steps1. Primary filtration and multi-media filter
2. Coagulation or flocculation
3. Desalination
4. Softening
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Chlorine removal
Activated-carbon (AC) filtration
or bisulphite1. AC removes chlorine but bacteria can then grow
2. AC filtration can remove organic impurities
3. Bisulphite leaves sulphate residues but is
anti-microbial
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raw water in
S trap to sewer
Water is keptcirculating
To water
softener &DI plant
cartridge
filter5 micrometers
activated
carbon
filter
spray ball
break tank
air break to draincentrifugal pump
air filter
float
operated
valve
sand filter
excess water recycled
from deioniser
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Water Softener schematicdrawing
brine and salt tank
brine
"hard" waterin
zeolite water softener
-exchanges-Ca and Mg for Na
drain
"soft" water to deioniserby pass valve
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Water purification
Remove particles, bacteria,
pyrogen, organic, inorganicions and silica
Reverse Osmosisraw water
High pressure
Feed
water
under
pressure
Reject
water
Semi-permeable
mem
brane
Permeate
water
drain or recycle
Low pressure
Purified water
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DeionizationRemove organic, inorganic ions, silica and carbon dioxide
Cationic column Anionic column
Hygienic pump
Outlets or storage.
Ozone generator
UV light
HCl NaOH
Eluates to
neutralization
plant
Air break to sewer
Drain line
from water softener
Water mustbe keptcirculating
1
2
3
4
5
6
1
2
3
4
5
6
Return to de-ioniser
Cartridge
filter 5 m
Cartridge
filter 1 m
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Water purificationDistillation Remove particles, bacteria, pyrogen, organic,
non-volatile, inorganic ions and silicafor WFIUltrafiltration Kill bacteria and breakdown TOC
Can be used for WFI or for Water For Final
Rinsing for parenteral manufacturing (if permitted)
Removes organic contaminants, such asendotoxins
Operation at 80C, and sterilization at 121 C
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Auto DIRO/Auto DI2 stages RO
Purified water9/20/2013 20
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Sampling
There must be a sampling procedure. Sample integrity must be assured.
Sampler training
Sample point
Sample size
Sample container
Sample label
Sample storage and transport Arrival at the laboratory
Start of test
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Sampling Point
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i i ifi i f
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Testing - setting specifications forpurified water
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Testing1. Method verification2. Chemical testing
3. Microbiological testing
test method
types of media used
incubation time and temperature
objectionable and indicator organisms
manufacturer must set specifications
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Water for Injections1. International pharmacopoeia requirements for WFI are
those for purified water plus it must be free from
pyrogens
2. Usually prepared by distillation
3. Storage time should be less than 24 hours
4. Microbial limits must be specified
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P d d i
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Pyrogens and endotoxins1. Any compound injected into mammals which gives
rise to fever is a Pyrogen
2. Endotoxins are pyrogenic, come from Gram negative
bacterial cell wall fragments
3. Detectendotoxins using a test forlipopolysaccharides
(LPS)
rabbit test detects pyrogens
LAL test detects endotoxins
4. Ultrafiltration, distillation, & RO may remove pyrogens
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Suggested bacterial limits (CFU /mL)Sampling location Target Alert Action
Raw water 200 300 500
Post multimedia filter 100 300 500
Post softener 100 300 500
Post activated carbon filter 50 300 500
Feed to RO 20 200 500
RO permeate 10 50 100Points of Use 1 10 100
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WHO t t t t id
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WHO water treatment guidance All water-treatment systems should be subject to:
planned maintenance validation
monitoring
Maintenance work should be documented
For reliable production, water treatment plants should be:
1. Designed
2. Constructed
3. Maintained
4. Operated within design limits
5. Controlled to prevent microbial growth9/20/2013 28
P h kli t id
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Prepare a checklist or an aide
memoire and review1. Water Quality Manual
2. Water system drawing
3. Validation
4. Sampling procedures, locations and plan
5. Records of testing
6. Sanitation and maintenance
7. Schedules of maintenance
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Reviewwater quality manual1. A water quality manual is advisable
2. A brief description of water systems is required
3. Include drawings of the purification, storage distribution
system (P&ID)
The water quality manual should show:
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pipelines
non-return (or check)
valvesbreather points
couplings
pipe slopes
Velocities
valves
sampling pointsdrain points
Instrumentation
flow rates
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Validation plan for a water system
1. Establishing standards for quality attributes and
operating parameters.
2. Defining systems and subsystems suitable to produce
the desired quality attributes from the available source
water.3. Selecting equipment, controls, and monitoring
technologies.
4. Developing an IQ stage consisting of instrument
calibration, inspection to verify that the drawingsaccurately depict the as built configuration of the water
system, and, where necessary, special tests to verify
that the installation meets the design requirements.
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5. Developing an OQ stage consisting tests and
inspection to verify that the equipment, system
alerts, and controls are operating reliably and thatappropriate alert and action levels are established.
This phase of qualification may overlap with
aspects of the next step.
6. Developing a prospective PQ stage to confirm theappropriateness of critical parameter operating
ranges. A concurrent or retrospective PQ is
performed to demonstrate system reproducibility
over an appropriate time period. During this phaseof validation, Alert and action levels for key quality
attributes and operating parameters are verified.
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7. Supplementing a validation maintenance program
(also called continuous validation life cycle) that
includes a mechanism to control changes to the water
system and establishes and carries out scheduled
preventive maintenance, including recalibration of
instruments.
8. In addition, validation maintenance includes a
monitoring program for critical process parameters
and a corrective action program.
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WATER SYSTEM VALIDATION LIFE CYCLE
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WATER SYSTEM VALIDATION LIFE CYCLE
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WATER SYSTEM VALIDATION
The operational considerations of water systems
including:
Start up, commissioning and qualification
Monitoring
Maintenance
System reviews
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Start up and commissioning Precursor to qualification and validation
Should be planned, well defined, well
documented
Includes setting to work
Includes system set-up
Includes recording of system performanceparameters
Controls loop tuning
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Q lifi ti
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Qualification WPU, PW, HPW and WFI systems are all considered
to be direct
impact, quality critical systems that should be
qualified.
The qualification should follow the validation
convention of design review ordesign qualification (DQ), installation qualification
(IQ), operational qualification (OQ) and performance
qualification (PQ).
DQ: Design review influenced by source water andrequired water quality
IQ: Installation verification of the system
OQ: operational qualification9/20/2013 37
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Performance Qualification (PQ)
Presentation focusing on PQ
PQ demonstrates consistent and reliable
performance of the system
Validation of water systems should consist of at
least three phases:
Phase 1: investigational phase;
Phase 2: short-term control; and
Phase 3: long-term control.9/20/2013 38
Phase 1
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Phase 1 A test period of 24 weeks - monitoring the system
intensively
System to operate continuously without failure or
performance deviation
The fo l lowing should be inc luded in the test ing
approach: Undertake chemical and microbiological testing in
accordance with a defined plan
Sample daily:
incoming feed-water
after each step in the purification process
each point of use and at other defined sample
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Phase 1
Develop: appropriate operating ranges
and finalize operating, cleaning, sanitizingand maintenance procedures
Demonstrate production and delivery of productwater of the required quality and quantity
Use and refine the standard operating procedures(SOPs) for operation, maintenance, sanitizationand troubleshooting
Verify provisional alert and action levels
Develop and refine test-failure procedure
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Phase 2
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Phase 2 A further test period of 24 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 duringthis phase
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
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Phase 3
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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 duringphases 1 and 2
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Ongoing system monitoring
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Ongoing system monitoring After Phase 3 system review needed
Based on review including results, establish a routinemonitoring plan
Monitoring to include a combination of on-line monitoring
and off- line sample testing
Data analysed for trends 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
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M i t
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MaintenanceA controlled, documented maintenance programme
covering:
Defined frequency with plan and instructions
Calibration programme
SOPs for tasks
Control of approved spares Record and review of problems and faults during
maintenance
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System review
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System review WPU (PW, HPW and WFI) systems to be reviewed atappropriate regular intervals
Review team includes engineering, QA, operations andmaintenance
The review to cover, e.g.
changes made since the last review;
system performance;
reliability; quality trends;
failure events;
investigations;
out-of-specifications results from monitoring; changes to the installation;
updated installation documentation;
log books; and
the status of the current SOP lists 45
Preventative Maintenance Program
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Preventative Maintenance Program
Pretreatment Component Example Activated
Carbon Unit
Item Suggested
Frequency
Consequences
Media Replacement 6 Months TOC and/or Chloramine
Breakthrough
Sanitize Column
Internals
6 Months Microbial Excursion
Replace Gaskets 2 Years Leak/Shutdown
Access Gaskets 6 Months Leak/Shutdown
Clean/Replace
Distributors
1 Year Failure Media in Product
Water
Instrument Calibration 1 Year Improper System Operation
Replace Valve
Diaphragms
2 Years Bypass/Cross Contamination
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Ion Removal Component Example RO Unit
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p p
Item Suggested
Frequency
Consequences
Rotate RO
Membranes
6 Months Loss in Product Water Flow Rate
and Quality (Chemical and TVB)
Contract Clean
Rotated
Membranes
6 Months Loss in Product Water Flow Rate
and Quality (Chemical and TVB)
ChemicalSanitization 6 Months TVB Excursions
Interconnector O-
Rings
6 Months Waste-to-Product Leak
End Fitting O-
Rings
6 Months Waste-to-Product Leak
Instrument
Calibration
1 Year Loss of System Control
Replace
Interconnectors
1 Year Waste-to-Product Leak
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Item Suggested Consequences
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Item Suggested
Frequency
Consequences
Replace Feed Water
Pump Seals
2 Years Pump Leak Introduction of
Air/Water TVB Increase
Vale Seals/Diaphragms 2 Years BypassSanitize Pressure
Vessels
6 Months TVB Excursions
Change Prefilters 1 Week Foulant Increase Resulting in TVB
Increase
Hot Water Sanitize (if
equipped)
2 Weeks TVB Excursions
Replace Rotated
Membranes
3 Years Loss in Product Water Flow Rate
and Quality (Chemical and TVB)
Repassivate 1-2 Years Rouging Biofilm TVB Increase
Derouge &
Repassivate
1-3 Years Rouging Biofilm TVB Increase
Hot Water Sanitization 1 Week
1 Month
TVB Excursions
Chemical Sanitization 6 Months Biofilm TVB Excursion9/20/2013 48
Storage & Distribution Loop Example USP
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Storage & Distribution Loop Example
USP
Purified Water Storage Tank (No Ozone)
Item Suggested
Frequency
Consequences
Instrument
Calibration
1 Year Loss of Level Control
Inspect Rupture
Disc
6 Months TVB Excursion
Replace Rupture
Disc
1 Year TVB Excursions
Replace
Hydrophobic Vent
Filter Cartridge
6 Months TVB Excursion
Inspect Tank
Interior
6 Months Rouging/Biofilm
Replace Manway
Gasket
1 Year TVB Excursion/Leak
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REFERENCE
WHO good manufacturing practices: water for
pharmaceutical use. Geneva, World Health
Organization 2005 (WHO Technical Report Series,
No. 929), Annex 3.
WHO Expert Committee on Specifications for
Pharmaceutical Preparations. Geneva, World Health
Organization 2006 (WHO Technical Report Series,
No. 937), Annex 4.
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