Water System
Supaporn Phumiamorn17-18 Jan, 2006
GMP course
Supaporn Phumiamorn, GMP course, 17-18 Jan,2006
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Topic
Water system - Objectives and Principles
- Storage, Treatment - Contaminants, Sampling Water system inspection
Supaporn Phumiamorn, GMP course, 17-18 Jan,2006
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Objectives
- Introduction to water for pharmaceutical use
- Sources and types of water for pharmaceutical use- Storage of bulk, untreated raw
water- Pre-treatment of water
Supaporn Phumiamorn, GMP course, 17-18 Jan,2006
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Principles
Like any starting material, water must conform to GMP norms.
It must be “potable and comply with WHO guidelines for drinking-water quality.
Supaporn Phumiamorn, GMP course, 17-18 Jan,2006
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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 required
Principles
Supaporn Phumiamorn, GMP course, 17-18 Jan,2006
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Water hardness
Water hardness mg/L or ppmClassification as CaCO3
Soft 0-60
Moderate 61-120
Hard 121-180
Very hard >180
Supaporn Phumiamorn, GMP course, 17-18 Jan,2006
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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
Supaporn Phumiamorn, GMP course, 17-18 Jan,2006
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Check cover- to keep out insects,
birds and animalsCheck contamination
Raw water storage
Supaporn Phumiamorn, GMP course, 17-18 Jan,2006
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1. Water for Injections – PFW & WFI2. Softened Water3. Water for Final Rinse4. Pure, or Clean Steam
5. Purified Water 6. Water for Cooling Autoclaves
Types of water used in pharmaceutical processes
Supaporn Phumiamorn, GMP course, 17-18 Jan,2006
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Pre-treatment steps
Primary filtration and multi-media filter
Coagulation of flocculation Desalination Softening
Water pre-treatment complex
External raw water
storage
Pretreatment room
Supaporn Phumiamorn, GMP course, 17-18 Jan,2006
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Chlorine removal
Activated-carbon (AC) filtration or bisulphite AC removes chlorine but bacteria can then
grow. AC filtration can remove organic impurities. Bisulphite leaves sulphate residues but is
anti-microbial.
Supaporn Phumiamorn, GMP course, 17-18 Jan,2006
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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
Supaporn Phumiamorn, GMP course, 17-18 Jan,2006
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Contaminants of water (1)
There is no pure water in nature, as it can contain up to 90 possible unacceptable contaminants
Contaminant groups:1. Inorganic compounds2. Organic compounds3. Solids 4. Gases5. Micro-organisms
Supaporn Phumiamorn, GMP course, 17-18 Jan,2006
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Contaminants of water (2)
Treatment depends on water’s chemistry and contaminants, influenced by:
1. Rainfall 5. Evaporation2. Erosion 6. Sedimentation3. Pollution 7. Decomposition4. Dissolution
Supaporn Phumiamorn, GMP course, 17-18 Jan,2006
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Contaminants of water (3)
Problem minerals 1. Calcium and magnesium 2. Iron and manganese3. Silicates4. Carbon dioxide5. Hydrogen sulfide6. Phosphates
Supaporn Phumiamorn, GMP course, 17-18 Jan,2006
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Further problem minerals 1. Copper2. Aluminium3. Heavy metals
– Arsenic, lead, cadmium4. Nitrates
Contaminants of water (4)
Supaporn Phumiamorn, GMP course, 17-18 Jan,2006
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Micro-organisms – Biofilm1. Algae2. Protozoa
– Cryptosporidium– Giardia
3. Bacteria– Pseudomonas– Gram negative, non-fermenting bacteria– Escherichia coli and coliforms
Contaminants of water (5)
raw water in
« S” trap to sewer
Water is kept circulating
To water softener & DI plant
Pretreatment – schematic drawing
cartridgefilter
5 micrometers
activatedcarbon
filter
spray ball
break tank
air break to draincentrifugal pump
air filter
floatoperated
valvesand filter
excess water recycledfrom deioniser
Plumbing
chlorinationS S S S
Pre-treatment Distillation
Holding Take
80oc
SPump
S
S
S
Source water
* S: Sampling
.
1.Filtration
-Sand filter-Charcoal filter-Cartridge filter
2. Primary water treatment
-Water solftener-Deionizer-Reverse Osmosis
brine and salt tank
brine
"hard" waterin
zeolite water softener-exchanges-Ca and Mg for Na
drain
"soft" water to deioniserby pass valve
Water Softener – schematic drawing
Water purification
Cartridge filtrationRO / Deionizer
Water purification
Remove particles, bacteria, pyrogen, organic, inorganic ions and silica
Reverse Osmosis
Water purification
Deionization
Remove organic, inorganic ions, silica and carbon dioxide
Water purification
Distillation
Remove particles, bacteria, pyrogen, organic, non-volatile, inorganic ions and silica for WFI
Water purification
Ultrafiltration
Kill bacteria and breakdown TOC
Auto DIRO/Auto DI2 stages RO
Purified water
-Conductivity meter- pH meter-Temperature meter(80oC)-Alarm meter
Supaporn Phumiamorn, GMP course, 17-18 Jan,2006
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Sampling
There must be a sampling procedure. Sample integrity must be assured. Sampler training Sample point Sample size Sample container
Supaporn Phumiamorn, GMP course, 17-18 Jan,2006
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Sample label
Sample storage and transport
Arrival at the laboratory
Start of test
Sampling
Supaporn Phumiamorn, GMP course, 17-18 Jan,2006
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Water for Injections
International pharmacopoeia requirements for WFI are those for purified water plus it must be free from pyrogens.
Usually prepared by distillation. Storage time should be less than 24
hours. Microbial limits must be specified.
Supaporn Phumiamorn, GMP course, 17-18 Jan,2006
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Pyrogens and endotoxins
Any compound injected into mammals which gives rise
to fever is a “Pyrogen”.
Supaporn Phumiamorn, GMP course, 17-18 Jan,2006
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WFI testing
Microbial test, < 1 CFU/10 ml WFI
Endotoxin test, < 0.25 Eu/ml
Total organic count, < 500 g/l
Supaporn Phumiamorn, GMP course, 17-18 Jan,2006
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Water system inspection
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Inspection plan
Water quality manual - water system drawing
- validation- sampling procedures, location and plan- records of testing- sanitation and maintenance- schedules of maintenance
Supaporn Phumiamorn, GMP course, 17-18 Jan,2006
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Review water quality manual
A water quality manual is advisable.
A brief description of water systems is required.
Include drawings of the purification, storage distribution system.
Supaporn Phumiamorn, GMP course, 17-18 Jan,2006
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The manual should contain
Chemical and microbiological specifications
Sampling instructions Test procedures Responsible persons Training requirements
Supaporn Phumiamorn, GMP course, 17-18 Jan,2006
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Review validation
Validation for water systemsconsists of 3 phases:Phase 1: 2-3 weeksPhase 2: 4 weeksPhase 3: 1 year
Supaporn Phumiamorn, GMP course, 17-18 Jan,2006
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Phase 1
Investigational phase (2-4 weeks)- DQ, IQ and OQ- Develop
- operational parameters- cleaning and sanitization
procedures and frequencies- Sample daily at each point of use-End of phase 1, develop SOPs for the
water system
Supaporn Phumiamorn, GMP course, 17-18 Jan,2006
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Phase 2
Verifying control (4- 5 weeks)
- Demonstrate the system is in control
-Sampling as in phase 1
Supaporn Phumiamorn, GMP course, 17-18 Jan,2006
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Phase 3
Verifying long- term control ( 1 year)
- Demonstrate the system in control over a long period of time
-Weekly sampling
Conducting the inspection Take the drawing and walk around the entire
system Check:
- dead legs - pumps-filter - UV light-pipe and fittings - sample points-DI - RO-storage tank - non return valves-by –pass lines - heat exchangers
Supaporn Phumiamorn, GMP course, 17-18 Jan,2006
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Check:- stainless steel – PVC and most plastics not recommended- water quality- hygienic couplings- passivation- air breaks or “Tundish”
Supaporn Phumiamorn, GMP course, 17-18 Jan,2006
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Check:- condition and equipment corrosion on plates of heat exchangers indicates possible contamination- maintenance records
Supaporn Phumiamorn, GMP course, 17-18 Jan,2006
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Check:- air filter- integrity testing, sterilization- replacement frequency- burst discs
Supaporn Phumiamorn, GMP course, 17-18 Jan,2006
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References
WHO,1997. Joint training on GMP for biological products in Thailand, 2-11 September, 1997
Chung Keel Lee, 2003. GMP and related topics, 13-15 October, 2003.
Chung Keel Lee, 2004. Current GMP for biological products and its practical implementation, 22-23 March, 2004.
FDA and WHO, 2004. GMP inspection workshop, 21-29 June, 2004.