VALIDATION OF WATER SYSTEMS FOR PHARMACEUTICAL USE

Prepared By: Vinay B. Patel Harshal Thakkar DEPARTMENT OF QUALITY ASSURANCE SHRI SARVAJANIK PHARMACY COLLEGE MEHSANA, GUJARAT
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A Seminar On

Introduction
Water is the most widely used substance, raw material or starting material in the production, processing and formulation 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 products.
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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 required

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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 5. Micro-organisms
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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 Organisms Biofilm

1. Algae
2. Protozoa Cryptosporidium Giardia 3. Bacteria Pseudomonas Gram negative, non-fermenting bacteria Escherichia coli and coliforms
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Turbidity
1. Silt, clay, and suspended material cause turbidity
2. Small particles include "colloids" 3. Removal of colloids is usually the first step in water treatment

Water hardness
mg/L or ppm as CaCO3 0-60 61-120 121-180 > 180
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Water hardness classification Soft Moderate Hard Very Hard

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Source of raw water

1. Rain water 2. Surface or ground water 3. Well or borehole 4. Municipal or civil tap 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 guidance

The following should be monitored Sources of water Treatment procedures Water treatment equipment Treated water tests

Monitoring records required

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Pre-treatment steps
1. 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 bisulphite

1. 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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float operated valve

excess water recycled from deioniser air filter sand filter

activated carbon filter

To water softener & DI plant

spray ball

Water is kept circulating

raw water in

break tank

air break to drain

centrifugal pump

cartridge filter 5 micrometers

S trap to sewer 9/20/2013 15

Water Softener schematic drawing

"soft" water to deioniser by pass valve brine and salt tank

brine

zeolite water softener -exchanges -Ca and Mg for Na

"hard" water in

drain

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Water purification
High pressure Low pressure

Reverse Osmosis
Purified water

Semi-permeable membrane

Feed water under pressure

raw water

Remove particles, bacteria, pyrogen, organic, inorganic ions and silica

drain or recycle

Reject water

Permeate water

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Deionization
Remove organic, inorganic ions, silica and carbon dioxide
from water softener HCl NaOH 6 5 4 3 2 1 6 5 4 3 2 1

Water must be kept circulatingUV light

Cationic column

Anionic column

Cartridge filter 5 m

Cartridge filter 1 m Ozone generator

Eluates to neutralization plant Hygienic pump Return to de-ioniser

Outlets or storage. Drain line Air break to sewer

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Water purification
Distillation

Remove particles, bacteria, pyrogen, organic, non-volatile, inorganic ions and silica for WFI Ultrafiltration 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 as endotoxins
Operation at 80C, and sterilization at 121 C
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Purified water
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Auto DI RO/Auto DI 2 stages RO

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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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Testing - setting specifications for purified water

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Testing
1. Method verification 2. 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 Injections

1. 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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Pyrogens and endotoxins

1. 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. Detect endotoxins using a test for lipopolysaccharides (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
Raw water

Target
200

Alert
300

Action
500

Post multimedia filter

Post softener Post activated carbon filter

100
100 50

300
300 300

500
500 500

Feed to RO
RO permeate Points of Use

20
10 1

200
50 10

500
100 100

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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.

2. 3. 4. 5.
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Designed Constructed Maintained Operated within design limits Controlled to prevent microbial growth
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Prepare a checklist or an aide memoire and review

1. 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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Review water quality manual

1. 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: pipelines non-return (or check) valves breather points couplings pipe slopes
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Velocities valves sampling points drain 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 drawings accurately 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 that appropriate 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 the appropriateness of critical parameter operating ranges. A concurrent or retrospective PQ is performed to demonstrate system reproducibility over an appropriate time period. During this phase of 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

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 performance parameters Controls loop tuning
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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 or design qualification (DQ), installation qualification (IQ), operational qualification (OQ) and performance qualification (PQ). DQ: Design review influenced by source water and required water quality IQ: Installation verification of the system OQ: operational qualification
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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.
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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 following should be included in the testing 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 points 9/20/2013 39

Phase 1
Develop: appropriate operating ranges and finalize operating, cleaning, sanitizing and maintenance procedures Demonstrate production and delivery of product water of the required quality and quantity Use and refine the standard operating procedures (SOPs) for operation, maintenance, sanitization and troubleshooting Verify provisional alert and action levels Develop and refine test-failure procedure
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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 during this 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
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 during phases 1 and 2

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Ongoing system monitoring

After Phase 3 system review needed Based on review including results, establish a routine monitoring 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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Maintenance
A 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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 WPU (PW, HPW and WFI) systems to be reviewed at appropriate regular intervals Review team includes engineering, QA, operations and maintenance 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 45 the status of the current SOP lists

System review

Preventative Maintenance Program

Pretreatment Component Example Activated Carbon Unit
Item Suggested Frequency Consequences

Media Replacement
Sanitize Column Internals Replace Gaskets

6 Months
6 Months 2 Years

TOC and/or Chloramine Breakthrough

Microbial Excursion Leak/Shutdown

Access Gaskets
Clean/Replace Distributors Instrument Calibration Replace Valve Diaphragms
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6 Months
1 Year 1 Year 2 Years

Leak/Shutdown
Failure Media in Product Water Improper System Operation Bypass/Cross Contamination
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Ion Removal Component Example RO Unit

Item
Rotate RO Membranes Contract Clean Rotated Membranes Chemical Sanitization Interconnector ORings End Fitting ORings

Suggested Frequency
6 Months 6 Months

Consequences
Loss in Product Water Flow Rate and Quality (Chemical and TVB) Loss in Product Water Flow Rate and Quality (Chemical and TVB) TVB Excursions Waste-to-Product Leak Waste-to-Product Leak

6 Months 6 Months 6 Months

Instrument Calibration
Replace Interconnectors
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1 Year
1 Year

Loss of System Control

Waste-to-Product Leak
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Item Replace Feed Water Pump Seals Vale Seals/Diaphragms Sanitize Pressure Vessels Change Prefilters Hot Water Sanitize (if equipped) Replace Rotated Membranes Repassivate

Suggested Frequency 2 Years 2 Years 6 Months 1 Week 2 Weeks 3 Years 1-2 Years

Consequences Pump Leak Introduction of Air/Water TVB Increase Bypass TVB Excursions Foulant Increase Resulting in TVB Increase TVB Excursions Loss in Product Water Flow Rate and Quality (Chemical and TVB) Rouging Biofilm TVB Increase

Derouge & Repassivate

Hot Water Sanitization Chemical Sanitization
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1-3 Years
1 Week 1 Month 6 Months

Rouging Biofilm TVB Increase

TVB Excursions Biofilm TVB Excursion
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Storage & Distribution Loop Example USP Purified Water Storage Tank (No Ozone)
Item Instrument Calibration Inspect Rupture Disc Replace Rupture Disc Replace Hydrophobic Vent Filter Cartridge Inspect Tank Interior Replace Manway Gasket
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Suggested Frequency 1 Year 6 Months 1 Year 6 Months

Consequences Loss of Level Control TVB Excursion TVB Excursions TVB Excursion

6 Months 1 Year

Rouging/Biofilm 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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