Water System: Water System Supaporn Phumiamorn
17-18 Jan, 2006 GMP course Topic: Topic
- Objectives and Principles
- Storage, Treatment
- Contaminants, Sampling
Water system inspection Objectives: Objectives - Introduction to water for pharmaceutical use
- Sources and types of water for
- Storage of bulk, untreated raw water
- Pre-treatment of water
Principles: Principles Like any starting material, water must conform to GMP norms.
It must be “potable and comply with WHO guidelines for drinking-water quality. Slide5: 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 Water hardness: Water hardness Water hardness mg/L or ppm
Classification as CaCO3
Very hard >180 Raw water storage: 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 Raw water storage: Check cover
- to keep out insects, birds and animals
Check contamination Raw water storage Slide9:
Water for Injections – PFW & WFI
Water for Final Rinse
Pure, or Clean Steam
Water for Cooling Autoclaves Types of water used in
Pre-treatment steps : Pre-treatment steps Primary filtration and multi-media filter
Coagulation of flocculation
Softening Slide11: Water pre-treatment complex
External raw water
storage Pretreatment room Chlorine removal: 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.
Why purify raw water?: Why purify raw water?
Although reasonably pure, it is always variable
Seasonal variations may occur in water
Some regions have very poor quality water
Must remove impurities to prevent product contamination.
Control microbes to avoid contaminating products Contaminants of water (1) : Contaminants of water (1) There is no pure water in nature, as it can contain up to 90 possible unacceptable contaminants
Micro-organisms Contaminants of water (2): Contaminants of water (2) Treatment depends on water’s chemistry and contaminants, influenced by:
1. Rainfall 5. Evaporation
2. Erosion 6. Sedimentation
3. Pollution 7. Decomposition
Contaminants of water (3): Contaminants of water (3) Problem minerals
Calcium and magnesium
Iron and manganese
Phosphates Slide17: Further problem minerals
Arsenic, lead, cadmium
Contaminants of water (4) Slide18: Micro-organisms – Biofilm
Gram negative, non-fermenting bacteria
Escherichia coli and coliforms Contaminants of water (5)
Slide19: raw water in « S” trap to sewer Water is kept circulating To water softener & DI plant Pretreatment – schematic drawing cartridge
5 micrometers activated
filter spray ball break tank air break to drain centrifugal pump air filter float
valve sand filter excess water recycled
from deioniser Plumbing: Plumbing chlorination S S S S Pre-treatment Distillation Holding
80oc S Pump S S S Source water * S: Sampling . 1.Filtration
-Cartridge filter 2. Primary water treatment
Reverse Osmosis Slide21: Water Softener – schematic drawing Water purification: Water purification Cartridge filtration RO / Deionizer Water purification: Water purification Remove particles, bacteria,
pyrogen, organic, inorganic ions and silica Reverse Osmosis Water purification: Water purification Deionization Remove organic, inorganic ions, silica and carbon dioxide Water purification: Water purification Distillation Remove particles,
bacteria, pyrogen, organic, non-volatile, inorganic ions
and silica for WFI Water purification: Water purification Ultrafiltration
and breakdown TOC Slide27: Auto DI
2 stages RO Purified water
Slide28: -Conductivity meter
- pH meter
-Alarm meter Sampling: Sampling There must be a sampling procedure.
Sample integrity must be assured.
Sample container Sampling: Sample label
Sample storage and transport
Arrival at the laboratory
Start of test Sampling Water for Injections: 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. Pyrogens and endotoxins: Pyrogens and endotoxins Any compound injected into mammals which gives rise to fever is a “Pyrogen”.
WFI testing: WFI testing Microbial test, < 1 CFU/10 ml WFI
Endotoxin test, < 0.25 Eu/ml
Total organic count, < 500 g/l Water system inspection: Water system inspection Inspection plan: Inspection plan Water quality manual
- water system drawing
- sampling procedures, location and plan
- records of testing
- sanitation and maintenance
- schedules of maintenance Review water quality manual : 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. The manual should contain: The manual should contain Chemical and microbiological specifications
Training requirements Review validation: Review validation Validation for water systems
consists of 3 phases:
Phase 1: 2-3 weeks
Phase 2: 4 weeks
Phase 3: 1 year Phase 1: Phase 1 Investigational phase (2-4 weeks)
- DQ, IQ and OQ
- 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 Phase 2 : Phase 2 Verifying control (4- 5 weeks)
- Demonstrate the system is in control
-Sampling as in phase 1 Phase 3: Phase 3 Verifying long- term control ( 1 year)
- Demonstrate the system in control over a long period of time
-Weekly sampling Conducting the inspection: Conducting the inspection Take the drawing and walk around the entire system
- dead legs - pumps
-filter - UV light
-pipe and fittings - sample points
-DI - RO
-storage tank - non return valves
-by –pass lines - heat exchangers Slide43: Check:
- stainless steel – PVC and most plastics not recommended
- water quality
- hygienic couplings
- air breaks or “Tundish” Slide44: Check:
- condition and equipment corrosion on plates of heat exchangers indicates possible contamination
- maintenance records Slide45: Check:
- air filter
- integrity testing, sterilization
- replacement frequency
- burst discs References: 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.