water system supaporn phumiamorn 17-18 jan, 2006 gmp course

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

Supaporn Phumiamorn, GMP course, 17-18 Jan,2006

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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.