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

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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

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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


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


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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Documents

Validation of Water System