water system supaporn phumiamorn 17-18 jan, 2006 gmp course
TRANSCRIPT
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Water System
Supaporn Phumiamorn17-18 Jan, 2006
GMP course
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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
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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
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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.
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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
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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
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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
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Check cover- to keep out insects,
birds and animalsCheck contamination
Raw water storage
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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
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Pre-treatment steps
Primary filtration and multi-media filter
Coagulation of flocculation Desalination Softening
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Water pre-treatment complex
External raw water
storage
Pretreatment room
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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.
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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 (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
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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
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Contaminants of water (3)
Problem minerals 1. Calcium and magnesium 2. Iron and manganese3. Silicates4. Carbon dioxide5. Hydrogen sulfide6. Phosphates
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Further problem minerals 1. Copper2. Aluminium3. Heavy metals
– Arsenic, lead, cadmium4. Nitrates
Contaminants of water (4)
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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)
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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
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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
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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
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Water purification
Cartridge filtrationRO / Deionizer
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Water purification
Remove particles, bacteria, pyrogen, organic, inorganic ions and silica
Reverse Osmosis
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Water purification
Deionization
Remove organic, inorganic ions, silica and carbon dioxide
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Water purification
Distillation
Remove particles, bacteria, pyrogen, organic, non-volatile, inorganic ions and silica for WFI
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Water purification
Ultrafiltration
Kill bacteria and breakdown TOC
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Auto DIRO/Auto DI2 stages RO
Purified water
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-Conductivity meter- pH meter-Temperature meter(80oC)-Alarm meter
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Sampling
There must be a sampling procedure. Sample integrity must be assured. Sampler training Sample point Sample size Sample container
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Sample label
Sample storage and transport
Arrival at the laboratory
Start of test
Sampling
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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.
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Pyrogens and endotoxins
Any compound injected into mammals which gives rise
to fever is a “Pyrogen”.
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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
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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
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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.
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The manual should contain
Chemical and microbiological specifications
Sampling instructions Test procedures Responsible persons Training requirements
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Review validation
Validation for water systemsconsists of 3 phases:Phase 1: 2-3 weeksPhase 2: 4 weeksPhase 3: 1 year
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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
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Phase 2
Verifying control (4- 5 weeks)
- Demonstrate the system is in control
-Sampling as in phase 1
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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
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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
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Check:- stainless steel – PVC and most plastics not recommended- water quality- hygienic couplings- passivation- air breaks or “Tundish”
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Check:- condition and equipment corrosion on plates of heat exchangers indicates possible contamination- maintenance records
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Check:- air filter- integrity testing, sterilization- replacement frequency- burst discs
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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.