PHARMACEUTICAL

WATER SYSTEM

20/05/2021 1

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 AGENDA

WATER CATEGORIES

MAJOR COMPONENTS

VALIDATION OR QUALIFICATION?

VALIDATION APPROACH

URS / IQ / OQ / PQ

MONITORING & RECAP

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 TYPES OF WATER USED IN
A PHARMACEUTICAL PLANT

MAJOR BASIC CATEGORIES

RAW WATER
POTABLE WATER
PURIFIED WATER
WATER FOR INJECTION

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 TYPES OF WATER USED IN
A PHARMACEUTICAL PLANT

MAJOR DEFINED CATEGORIES

POTABLE WATER
PURIFIED WATER
WATER FOR INJECTION

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 LOWEST GRADE IS “RAW WATER”

HIGHEST GRADE IS “WATER FOR INJECTION”

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 FACTORS THAT DISTINGUISH THE VARIOUS
CATEGORIES

are
Types of impurities present in water

Impurities fall in three groups

1. SUSPENDED IMPURITIES – (PARTICULATES)

2. DISSOLVED IMPURITIES - (ORGANIC & INORGANIC CHEMICALS;

GASES)

3. MICROBIOLOGICAL IMPURITIES - (PATHOGENS; PYROGENS) 6

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PROGRESSIVE WAY OF PURIFICATION

RAW POTABLE PURIFIED WFI

WATER WATER WATER

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 RAW WATER TO POTABLE
• Coagulation , Flocculation and Clarification
RAW • removal of suspended solids and turbidity from water
WATER

• Softening
• Color and Odor removal
HARD
WATER • Removal of Calcium , Magnesium and Silica

• Disinfection
• Removal of Micro organism
SOFT
WATER

• Drinkable Water
POTABLE
WATER
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 Coagulation , Flocculation
THE PRIMARY PURPOSE OF THE COAGULATION/FLOCCULATION PROCESS IS THE
REMOVAL OF TURBIDITY FROM THE WATER. TURBIDITY IS A CLOUDY APPEARANCE OF
WATER CAUSED BY SMALL PARTICLES SUSPENDED THEREIN.

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 POTABLE TO PURIFIED
• SAND FILTER / ACF
POTABLE
• removal of suspended solids and turbidity from water

• DE IONIZATION / RO
MINERAL • Removal of all cations and anions
REMOVAL

• MICRO / ULTRA / RO FILTRATION

• Removal of Micro organism and other injected chemicals
CFU
REMOVAL

• Purified Water
UV /
OZONE
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 MAJOR COMPONENTS

SAND FILTER ACTIVATED CARBON FILTER

To ACF
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STORAGE TANK – RAW WATER

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20/05/2021 13
UV LAMPS
In order to kill microorganisms, the UV rays must
actually strike the cell. UV energy penetrates the
outer cell membrane, passes through the cell
body and disrupts its DNA preventing
reproduction.

UV treatment does not alter water chemically;

nothing is being added except energy.

Most viruses are inactivated by doses of UVC at

254nm of between 1.0-10.0 mWsec/cm²

The dosage, a product of UV light intensity and

exposure time, is measured in microwatt second
per square centimeter (µws/cm²)

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 UV DISINFECTION PLANTS

• FLOW RATE: 1-11 M³/H* OPERATING TEMPERATURE: 5-25°C

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20/05/2021 16
EDI

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 RO, UF, OTHER FILTERS
PIPING , TANK,
CONTROL SYSTEM, LOOP

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FILTERS , PUMPS

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 VALIDATION ? QUALIFICATION

• QUALIFICATION IS FOR A PARTICULAR COMPONENT

• VALIDATION IS FOR A SYSTEM

• VALIDATION IS DONE GENERALLY ON AN EQUIPMENT WHICH CAN
PERFORM ONE OR MORE UNIT OPERATION WHOSE OUT PUT CAN
BE MEASURED

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IF WE DO NOT KNOW THE OUTCOME
IT IS A TRIAL

IF WE KNOW THE OUTCOME

IT IS A VALIDATION

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 VALIDATION APPROACH

• VALIDATION PROTOCOLS
• URS
• DQ
• IQ
• OQ
• PQ
• MAINTENANCE
• REVALIDATION
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 Protocol development
• IDENTIFICATION OF THE PROCESS TO BE VALIDATED

• IDENTIFICATION OF QUALITY OF WATER TO BE PRODUCED

• ROLES AND RESPONSIBILITIES OF CFT ON VALIDATION

• COMPLETE DESCRIPTION OF THE MAJOR COMPONENTS AND PROCESS

• RELEVANT SPECIFICATIONS OF WATER AFTER EACH STEP

• OBJECTIVE AND MEASURABLE CRITERIA FOR A SUCCESSFUL VALIDATION

• LENGTH AND DURATION OF THE VALIDATION

• SHIFTS, OPERATORS, EQUIPMENT TO BE USED IN THE PROCESS

• IDENTIFICATION OF OPERATORS AND REQUIRED OPERATOR QUALIFICATION

• IDENTIFICATION OF UTILITIES AND QUALITY OF THE UTILITIES

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 PROTOCOL DEVELOPMENT ..

• PROCESS PARAMETERS TO BE MONITORED

• METHODS FOR CONTROLLING AND MONITORING
• DEFINITION OF WHAT CONSTITUTES NON-CONFORMANCE FOR BOTH MEASURABLE
AND SUBJECTIVE CRITERIA
• METHODS (STATISTICAL ) FOR DATA COLLECTION AND ANALYSIS
• SAMPLING PLAN
• SANITIZATION REQUIREMENT AND METHODS
• CGMP AND SAFETY TESTS
• TESTS FOR REGULATORY REQUIREMENTS
• CONSIDERATION OF MAINTENANCE AND REPAIRS OF THE SYSTEM
• CRITERIA FOR REVALIDATION
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 URS ???
• OVERALL REQUIREMENT
• PROCURE AND COMMISSION A FULLY AUTOMATED PURIFIED WATER
SYSTEM TO PRODUCE USP XX GRADE PURIFIED WATER @ 10,000 LITERS
PER HOUR

• OPERATIONAL REQUIREMENT
• PRE TREATMENT SYSTEM
• RO / DI
• TOC REQUIREMENT
• ALERT AND ACTION LIMITS
• FUNCTIONAL REQUIREMENT
• AUTO / MANUAL
• POWER FAILURE / RESTART / RECOVERY
• EMERGENCY SAFETYT STOPS
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• ALARAM AND WARNINGS 25
 URS – CONTD..
• DATA SECURITY REQUIREMENT
• USER INTERFACE WITH OPERATOR AND SUPERVISOR
• 21 CFR PART 11 REQUIREMENT
• DATA STORAGE, RETENTION AND RECOVERY
• LANGUAGE REQUIREMENT
• DISPLAY & MIMIC REQUIREMENT
• INTERFACE WITH OTHER EQUIPMENT REQUIREMENT
• DATA COLLECTION AND RECORDING REQUIREMENT
• ENVIRONMENT REQUIREMENT
• LAY OUT REQUIREMENT
• WATER ROOM REQUIREMENT
• ELECTRICAL RATING REQUIREMENT
• EFFLUENT TREATMENT REQUIREMENT
• SEISMIC ZONE REQUIREMENT
• SANITIZATION REQUIREMENT
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 URS – CONTD..

• UTILITY REQUIREMENT
• MILESTONE AND TIMELINE REQUIREMENT
• SAFETY REQUIREMENT
• GMP REQUIREMENT
• DOCUMENT REQUIREMENT
• VALIDATION REQUIREMENT

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 URS – THE REQUIREMENTS
• WATER DEMAND PROFILE
• WATER SPECIFICATION NEED
• HOW WATER TO BE PRODUCED
• HOW WATER TO BE STORED
• HOW WATER TO BE DISTRIBUTED
• HOW WATER TO BE SAMPLED
• HOW WATER PLANT TO BE OPERATED
• WHAT DOCUMENTS REQUIRED 20/05/2021 28
 GEP

• DOCUMENTATION IS DEVELOPED TO PROVIDE EVIDENCE

OF THE DESIGN, AND THAT THE WATER SYSTEM
OPERATES IN ACCORDANCE WITH THE DESIGN.

• THIS DOCUMENTATION ENCOMPASSES DESIGN BASIS,

ENGINEERING, INSTALLATION, INSPECTION,
COMMISSIONING, QUALIFICATION AND OTHER
REVALIDATION REQUIREMENT

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 DOCUMENTATION - GENERIC
• A SYSTEM DESCRIPTION STATING DESIGN INTENT

• A SCHEMATIC DRAWING OF THE SYSTEM (P&ID)

• WRITTEN SYSTEM SPECIFICATIONS

• DETAILED DESIGN DRAWINGS

• VENDOR MANUALS AND DRAWINGS

• CALIBRATION CERTIFICATES

• SYSTEM QUALIFICATION TEST RESULTS

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 DOCUMENTATION - SPECIFIC
• ISOMETRIC DIAGRAM INDICATING LOCATION AND NUMBERING OF WELDS, RELATIVE
ELEVATIONS, SLOPE OF LINES, AND POINTS OF DRAINAGE.

• THE SYSTEM SPECIFICATION SHOULD INDICATE PERFORMANCE CRITERIA, AS WELL AS

DESIGN PARAMETERS
• FIELD INSPECTION AND TEST REPORTS SHOULD INCLUDE
• CLEANING AND PASSIVATION PROCEDURE AND RECORD
• WELD PARAMETER DOCUMENTATION AND INSPECTION REPORTS
• SLOPE VERIFICATION, AND VERIFICATION OF THE ABSENCE OF “DEAD-LEGS”

• SYSTEM QUALIFICATION TESTS RESULTS SHOULD BE REPORTED IN DIRECT COMPARISON TO

ACCEPTANCE CRITERIA DERIVED FROM SYSTEM DESIGN AND OPERATING SPECIFICATIONS

• SYSTEM QUALIFICATION SHOULD INCLUDE VERIFICATION OF ALL AUTOMATED FUNCTIONS,

SPECIFIED TEMPERATURE CONTROL, DISTRIBUTION SYSTEM VELOCITY, AND INITIAL WATER
QUALITY DETERMINATION
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 CONSTRUCTION DOCUMENTATION:
• “AS-BUILT” CAD PIPING P&I DS
• “CONTROL COPY” OF PIPING ISOMETRIC DRAWINGS
• PRESSURE TEST REPORTS
• WELD PROCEDURE QUALIFICATION
• WELDER QUALIFICATION RECORDS AND LOGS
• PURGE GAS CERTIFICATE OF PURITY
• MATERIAL RECEIVING AND INSPECTION REPORTS AND LOGS
• MATERIAL TEST REPORTS (MTRS)
• DAILY WELDING REPORTS
• SLOPE VERIFICATION ON ISOMETRIC DRAWINGS
• WELD COUPON LOG
• WELD INSPECTION REPORTS
• CLEANING/PASSIVATION DOCUMENTATION
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• OPERATION AND MAINTENANCE MANUALS
• PURCHASED PROCESS EQUIPMENT
• PURCHASED INSTRUMENTATION

• HYDROSTATIC TESTING

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 Water for injection as per United States Pharmacopoeia (USP)

Sr. No.
Test Specification

1. Clear, colourless liquid; odourless.

Description

2. Not more than 500 ppb

Total organic carbon

3. Less than 1.3 µS/cm

Conductivity (at 25°C)

4. Less than 0.25 EU/mL

Bacterial Endotoxins

5. Microbial Limit test

a. Total aerobic microbial count Less than 10 cfu/100 mL

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 Water for injection as per European Pharmacopoeia (Ph. Eur.)

Test Specification

Clear and colourless liquid.

Appearance

Maximum 0.5 mg/L

Total organic carbon

Less than 1.3 µS/cm

Conductivity (at 25°C)

Less than 0.25 IU/mL

Bacterial Endotoxins

Microbial Limit test

Total aerobic microbial count Less than 10 cfu/100 mL

Nitrates Maximum 0.2 ppm

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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 50 100
Points of Use 1 10 100
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 EVALUATION & DESIGN OF
A WATER SYSTEM

• RELIABLE DATA AND INFORMATION

• WATER RESOURCE AVAILABLE

• RAW WATER ANALYSIS – ALL SEASONAL

• WATER CONSUMPTION PROFILE OF THE PLANT

• TYPE OF WATER REQUIREMENT

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 DESIGN DEVELOPMENT
• PHYSICAL DIMENSION OF SYSTEM

• SELECTION OF SUITABLE EQUIPMENT

• EQUIPMENT ARRANGEMENT AND OPERATING SEQUENCE

• DEVELOPMENT OF PROCESS FLOW DIAGRAMS

• AUTOMATION REQUIREMENT
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 TYPICAL WATER SYSTEM INSTALLATIONS
• PRETREATMENT

• 2-BED DE-IONIZING (DI) UNIT

• REVERSE OSMOSIS (RO) UNIT

• ULTRA FILTRATION ( UF ) UNIT

• COMBINATION OF ABOVE

• RO /EDI /CDI

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 DO U DO DQ?
• CHECKING THE DESIGN FOR MEETING THE REQUIREMENT
• DECIDING THE BEST OPTION AND FREEZING
• COMPONENT WISE DETAILING AND DECIDING THE FLOW OF WATER

FAT ?
• FAT Protocol preparation and approval
• What you will check? Interlocks? Certificates?
• What about RAW WATER? Is it same as yours?
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 DQ

• ICH Q7A DEFINES DQ AS DOCUMENTED VERIFICATION THAT THE PROPOSED

DESIGN OF THE FACILITIES, SYSTEM AND EQUIPMENT IS SUITABLE AND IN
ACCORDANCE WITH THE CGMP REQUIREMENT.

WHY DQ?

• IT IS THE FIRST ELEMENT OF THE VALIDATION OF THE FACILITIES, SYSTEM AND

EQUIPMENT
• THE “ COULD, SHOULD AND USUALLY ARE GUIDANCE DOCUMENTS ONLY , NOT
REGULATIONS.
• GOVT. GUIDANCE DOCUMENTS ARE WORST THAN REGULATIONS IN A SENSE
• THERE FORE, MANY COMPANIES ARE IMPLEMENTING DQ TO AVERSE THE RISK AND
EXPECT OTHERS ( AUDITORS , PEER COMPANIES ) TO SUPPORT THESE EFFORTS.

41
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 FOR A DQ TO BE VALID ,
IQ, OQ & PQ NEED TO BE PERFORMED
ON THE FACILITY, SYSTEM AND EQUIPMENT
THAT WAS CONSTRUCTED AS PER THE

DESIGN THAT WAS QUALIFIED

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METHODS OF
INSPECTION

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 VISUAL INSPECTION
For fittings and process components including, but not
limited to, tubing, valves, pumps, filter housings, and
instrumentation, each item shall be visually examined
for the following criteria, as a minimum. It is not a
requirement that the packaged components be removed
from the original packaging, provided the following can
be verified:
(a) manufacturer’s name, logo, or trademark
(b) alloy/material type
(c) description including size and configuration
(d) heat number/code
(e) product contact surface finish symbol
(g) pressure rating for valves
(h) no damage or other non-compliances
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 VERIFICATION OF MATERIAL TEST
REPORTS

for fittings and process components including, but not limited to,
tubing, valves, pumps, filter housings, and instrumentation, shall be
examined for the following criteria, as a minimum:

• Material Test Report verified to the applicable specification(s)

• heat number/code traceable to a Material Test Report

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 PHYSICAL EXAMINATION

• A PERCENTAGE OF EACH LOT MAY BE PHYSICALLY EXAMINED

BY THE MANUFACTURER / OWNER / USER FOR THE FOLLOWING
CRITERIA:

(A) WALL THICKNESS (FOR WELD ENDS ONLY)

(B) OUTSIDE DIAMETER (OD) (FOR WELD ENDS ONLY)
(C) SURFACE FINISH (AS SPECIFIED)
(D) VISUAL
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 WHAT SHOULD WE LOOK FOR?
CLEANLINESS AND ORGANIZATION

• IN WATER GENERATING AREA

• WATER STORAGE AREA
• AT EQUIPMENT

INTEGRITY OF CRITICAL PARTS AND INSTRUMENTS:

• OPERATION
• CALIBRATION
• READINGS
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LEAKS AND DRIPS AT

• PUMPS,
• VALVES,
• JOINTS,
• SAMPLING PORTS

PHYSICAL CONDITION, DRYNESS, SOILING,

STORAGE FOR

• TEMPORARY OR REMOVABLE CONNECTION PIECES

• FLEXIBLE HOSES,
• VENT FILTERS

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ACCESSABILITY:

• SAMPLING PORTS,
• USER POINT VALVES
• INSTRUMENTS AND ACCESSORIES

DRAIN-OFF POINTS

• AT EQUIPMENT WHERE CONNECTIONS FORM DEAD LEGS

• SAMPLING PORTS

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 CONDUCTING THE INSPECTION (1)

• Take the drawing and walk around the entire system

• Check for :
– dead legs
– filter
– pipes and fittings / Valves
– DI
– storage tanks
– by-pass lines
– Pumps
– UV lights
– Sample Points
– RO / Storage Tanks / CIP Tanks

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 CONDUCTING THE INSPECTION (2)

• Check pipes and pumps

– hygienic couplings
– welded pipes / Screwed joints not allowed
– hygienic pumps
– hygienic sampling points
– acceptable floor
– no leaks

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 INSTALLATION QUALIFICATION (IQ)
IQ MEANS IS IT INSTALLED CORRECTLY?
IMPORTANT IQ CONSIDERATIONS ARE:

• THE INSTALLATION QUALIFICATION APPROACH;

✓ CONFIRMATION OF COMPLETION OF COMMISSIONING

✓ IQ PROTOCOL APPROVAL

✓ PROTOCOL MODIFICATIONS LOG

✓ PROTOCOL MODIFICATIONS
✓ PROTOCOL DEVIATION LOG
✓ PROTOCOL DEVIATIONS
✓ PROTOCOL PRE-EXECUTION SIGNATURE LIST/TRAINING VERIFICATION

✓ PHYSICAL VERIFICATION OF APPROVED P&IDS 20/05/2021 52

✓ EQUIPMENT DESIGN FEATURES (I.E. MATERIALS OF CONSTRUCTION

CLEANABILITY, NAMEPLATE DETAILS ETC.)
 IQ CONTD..

✓ INSTALLATION CONDITIONS (LAYOUT, WIRING, UTILITIES,

FUNCTIONALITY, ETC.)
✓ SUPPLIER DOCUMENTATION, PRINTS, DRAWINGS AND MANUALS
✓ SOFTWARE DOCUMENTATION
✓ SPARE PARTS LIST
✓ ENVIRONMENTAL CONDITIONS (SUCH AS CLEAN ROOM
REQUIREMENTS, TEMPERATURE, HUMIDITY)
✓ IQ SUMMARY AND CLEARANCE TO PROCEED TO OQ

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 AS-BUILT P&ID DRAWING VERIFICATION FORM
Objective: To confirm accuracy of all system P&ID drawings associated with this project.
Acceptance Criteria: System P&ID drawings must be reviewed, verified, and updated as required to reflect the “As-Built”
condition of the system.
Test Procedure: Obtain working copies of the latest revision of each system P&ID drawing listed below. Compare the
drawing with the installed system, annotate drawing details that are correct with a green highlighter, and note any
discrepancies that are discovered in red. Focus upon only those sections of the drawing that falls within the scope of this
protocol. Once complete, annotate the verified drawings "As-Built", sign, date, and attach a copy to the completed IOQ
Protocol Test Report. Submit the original, verified drawings to Engineering for revision where discrepancies are noted.

References Required: As-Built P&ID Drawings

Title P&ID No Revision Date Inspected By / Date

Deviation Report Required (Yes/No) _________

Acceptance Criteria Met: (Yes/No):__________
Comments:
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Reviewed By System Owner: Date:

Approved By Validation/QA: Date:
 OQ

THE OQ SHALL BE DONE IN THREE STEPS

STEP 1:
GENERAL REQUIREMENTS REVIEW AND NON COMPLIANCES IF ANY

STEP 2:

SYSTEM-SPECIFIC FUNCTIONAL TESTS THAT ARE DESIGNED TO TEST THE CRITICAL COMPONENTS OF THE SYSTEM AGAINST SPECIFIED ACCEPTANCE
CRITERIA.

STEP 3:

VERIFICATION OF SOPS AND OPERATIONAL TRAINING

VERIFICATION OF PREVENTATIVE MAINTENANCE AND CALIBRATION PROGRAMS

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 PROCESS OF OQ
• CONFIRMATION OF COMPLETION OF IQ
• OQ PROTOCOL APPROVAL
• PROTOCOL MODIFICATIONS LOG
• PROTOCOL MODIFICATIONS
• PROTOCOL DEVIATION LOG
• PROTOCOL DEVIATIONS
• PROTOCOL PRE-EXECUTION SIGNATURE LIST/TRAINING VERIFICATION

• EXECUTION OF OQ
• TEST INSTRUMENT CALIBRATION VERIFICATION
• CRITICAL INSTRUMENT CALIBRATION VERIFICATION
• CGMP CRITICAL ALARM AND INTERLOCK VERIFICATION
• SYSTEM FUNCTIONAL TESTING
• STANDARD OPERATING PROCEDURE VERIFICATION
• TRAINING RECORD VERIFICATION
• PREVENTATIVE MAINTENANCE PROGRAM VERIFICATION
• CALIBRATION PROGRAM VERIFICATION
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• QUALIFICATION ACCEPTANCE CRITERIA SUMMARY
 QUALIFICATION ACCEPTANCE CRITERIA SUMMARY
Objective: To document that all criteria have been satisfied for the Qualification.
Acceptance Criteria: All criteria have been satisfied for Operational Qualification.
Test Procedure: Review the Operational Qualification section of this document and indicate whether all criteria have been
satisfied according to the table below. Indicate if any outstanding issues would prevent the protocol from being completed.
Acceptance Criteria Results Acceptable Verified By / Date
(Yes/No)
All critical open punchlist items identified have been closed
or a deviation report has been issued to document the open
item.
All test instruments are within calibration.
All critical instrumentation is within calibration.
cGMP alarms and interlocks function as specified.

The equipment components operate as specified.

SOPs to support equipment operation are available.

System Training has been completed.

Critical Components placed in the PM program.
Critical Components placed in the Calibration program.

All deviations that could impact the results of Qualification

have been resolved prior to proceeding to PQ or process
validation.
Deviation Report Required (Yes/No) _________
Acceptance Criteria Met: (Yes/No):__________
Comments:
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Reviewed By System Owner: Date:

Approved By Validation/QA: Date:
PERFORMANCE QUALIFICATION - (PQ)
In this phase the key objective is to demonstrate the process will
consistently produce acceptable product under normal operating
conditions

• PROTOCOL MODIFICATIONS LOG & PROTOCOL MODIFICATIONS

• PROTOCOL DEVIATION LOG & PROTOCOL DEVIATIONS
• PROTOCOL PRE-EXECUTION SIGNATURE LIST/TRAINING VERIFICATION
• OQ COMPLETION VERIFICATION
• TEST INSTRUMENT CALIBRATION VERIFICATION
• CRITICAL INSTRUMENTATION CALIBRATION VERIFICATION
• SYSTEM PERFORMANCE TESTING VERIFICATION
• SYSTEM CHALLENGE TEST
• PQ ACCEPTANCE CRITERIA SUMMARY
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 ONE OF THE OUTPUTS OF OQ AND PQ IS THE DEVELOPMENT OF ATTRIBUTES FOR CONTINUOUS
MONITORING AND MAINTENANCE. PROCESS AND PRODUCT DATA SHOULD ALSO BE ANALYZED TO
IDENTIFY ANY VARIATION DUE TO CONTROLLABLE CAUSES. DEPENDING ON THE NATURE OF THE PROCESS
AND ITS SENSITIVITY, CONTROLLABLE CAUSES OF VARIATION MAY INCLUDE:

• TEMPERATURE
• SEASONAL CHANGES
• ENVIRONMENTAL CONTAMINANTS
• PURITY OF PROCESS WATER
• VARIATIONS IN UTILITY SUPPLY
• VIBRATION OF MACHINES
• HUMAN FACTORS (TRAINING, ERGONOMIC FACTORS, STRESS, ETC.)
• VARIABILITY OF TREATMENT CHEMICALS AND CONSUMABLES
• WEAR AND TEAR OF EQUIPMENT

APPROPRIATE MEASURES SHOULD BE TAKEN TO ELIMINATE CONTROLLABLE CAUSES OF VARIATION.

ELIMINATING CONTROLLABLE CAUSES OF VARIATION WILL REDUCE VARIATION IN THE PROCESS OUTPUT
AND RESULT IN A HIGHER DEGREE OF ASSURANCE THAT THE OUTPUT WILL CONSISTENTLY MEET
SPECIFICATIONS.
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 FINAL REPORT

AT THE CONCLUSION OF VALIDATION ACTIVITIES, A FINAL REPORT

SHOULD BE PREPARED. THIS REPORT SHOULD SUMMARIZE AND
REFERENCE ALL PROTOCOLS AND RESULTS. IT SHOULD DERIVE
CONCLUSIONS REGARDING THE VALIDATION STATUS OF THE
PROCESS. THE FINAL REPORT SHOULD BE REVIEWED AND
APPROVED BY THE VALIDATION TEAM AND APPROPRIATE
MANAGEMENT.

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 EXAMPLES OF REASONS FOR REVALIDATION

REVALIDATION MAY BE NECESSARY UNDER SUCH CONDITIONS AS:

• CHANGE(S) IN THE ACTUAL PROCESS THAT MAY AFFECT QUALITY OR ITS VALIDATION
STATUS
• NEGATIVE TREND(S) IN QUALITY INDICATORS
• CHANGE(S) IN THE COMPONENT PERFORMANCE WHICH AFFECTS THE PROCESS
• TRANSFER OF PROCESSES FROM ONE LOCATION TO ANOTHER

THE NEED FOR REVALIDATION SHOULD BE EVALUATED AND DOCUMENTED. THIS

EVALUATION SHOULD INCLUDE HISTORICAL RESULTS FROM SAMPLING RESULTS,
CHANGES IN EXTERNAL REQUIREMENTS (REGULATIONS OR STANDARDS) AND OTHER
SUCH CIRCUMSTANCES.
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 SYSTEM MONITORING
AND CONTROL

TWO CATEGORIES OF MONITORING

• MONITORING FOR QUALITY

• MONITORING FOR OPERATION AND MAINTENANCE

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ENVIRONMENTAL MONITORING - QUALITY

✓ TOTAL ORGANIC CARBON

✓ CONDUCTIVITY / PH

✓ MICROBIAL CONTAMINANTS

✓ ENDOTOXIN

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ENVIRONMENTAL MONITORING – O & M

✓ PRESSURE

✓ TEMPERATURE

✓ FLOW / VELOCITY / QUANTITY

✓ CONDUCTIVITY / PH

✓ EFFICIENCY

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 TYPES OF INSTRUMENTATION
• INDICATING
• RECORDING (STORAGE OR PRINT)
• CAUTIONARY [ALERT; WARNING (AUDIO OR VISUAL)]
• CONTROLLING

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 SYSTEM OPERATING CONTROLS

• DEDICATED CONTROLS FOR EACH EQUIPMENT OR SKID

• A SIMPLE CONTROLLER THAT TIES UP FUNCTIONS OF SEVERAL DEDICATED

CONTROLLERS AND MAKES THEM OPERATE AS A SINGLE SYSTEM ( SCADA )

• A TOTALLY INTEGRATED CENTRAL CONTROL SYSTEM (DCS)

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 GENERAL MONITORING
CONSIDERATIONS

• MONITORING FREQUENCIES AND STRATEGIES

• ESTABLISHMENT OF A MEANINGFUL AND MANAGEABLE
PROGRAM

• SAMPLING MASTER PLAN AND TESTING

PROCEDURES
• ESTABLISHMENT OF EFFECTIVE ALERT AND ACTION
LIMITS
• TRENDING OF RESULTS 20/05/2021 67
• A WATER TESTING PLAN SHALL BE ESTABLISHED TO QUANTIFY SYSTEM
PERFORMANCE, INCLUDING SEASONAL EFFECTS, AND SHALL BE PART OF THE
WATER SYSTEM VALIDATION.
• OPERATIONAL QUALIFICATION (OQ)* TESTING IS TYPICALLY PERFORMED DAILY
DURING THE FIRST MONTH OF VALIDATION.
• DURING PERFORMANCE QUALIFICATION (PQ)*, AN ADDITIONAL MONTH OF
DAILY SAMPLING IS PERFORMED FOLLOWED BY LESS INTENSIVE SAMPLING
DURING THE REMAINING MONTHS.
• PQ IS CONDUCTED OVER A PERIOD OF ONE FULL YEAR TO ASSESS THE POTENTIAL
EFFECTS OF SEASONAL CHANGES ON THE WATER SYSTEM.
• DATA ACQUIRED DURING THE YEAR SHALL BE SUMMARIZED AND ANALYZED AT
LEAST EVERY TWO MONTHS, AND SHALL BE USED TO ESTABLISH ALERT AND
ACTION LEVELS BASED ON PROCESS CAPABILITIES.
• WATER DATA SHALL CONTINUE TO BE RECORDED, ANALYZED, AND TRENDED AS
THE DATA ARE COLLECTED BY THE SITE QUALITY AUTHORITY.

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 MONITORING
• A DOCUMENTED AND APPROVED* MONITORING PROGRAM FOR ALL TYPES OF WATER SHALL
BE ESTABLISHED AND INCLUDE, AT LEAST, THE FOLLOWING:

1. FREQUENCY OF SAMPLING AND TESTING

2. ACCEPTANCE CRITERIA (E.G., ALERT LEVELS*, ACTION LEVELS*, AND SPECIFICATIONS) FOR PHYSICAL,
CHEMICAL, AND MICROBIOLOGICAL ATTRIBUTES, AS APPLICABLE TO THE INTENDED USE OF THE WATER

3. MINIMAL TESTING FOR PURIFIED WATER( PW ) SHALL BE TOC, CONDUCTIVITY, AND CFU

4. MINIMAL TESTING FOR PW AND WFI SHALL BE ALL TESTS REQUIRED FOR PW PLUS BACTERIAL ENDOTOXIN
TESTING (BET);

5. DOCUMENTATION AND REVIEW OF WATER MONITORING RESULTS, THAT INCLUDE TRENDING*; AND
6. DOCUMENTED INVESTIGATIONS*, INCLUDING CORRECTIVE ACTIONS, WHEN ACCEPTANCE CRITERIA ARE
EXCEEDED.
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 SAMPLING PLAN
Water Type Minimum Sampling Frequency1
Water Used in Early & Daily - rotating sampling locations so that all locations are
Intermediate API Steps sampled at least Weekly.

Water Used in Final Steps Daily - rotating sampling locations so that all Use Points are
of API Process sampled at least every week.

PW, or WFI Daily - rotating sampling locations so that all locations are
sampled at least Weekly.

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 NOTES

1. ALL SAMPLES SHALL BE TESTED FOR MICROORGANISM COUNTS . PURIFIED WATER AND WFI SAMPLES
SHALL ALSO BE TESTED FOR BET. WHERE ON-LINE CONDUCTIVITY AND TOTAL ORGANIC CARBON PROBES
ARE USED WITH ESTABLISHED ALERT AND ACTION LEVELS, CHEMICAL TESTING FREQUENCY MAY BE LESS
FREQUENT AND IS BASED ON VALIDATED INTERVALS.
2. WHERE THE TYPE OF WATER USED AT A SAMPLING LOCATION CHANGES WITH THE MANUFACTURING STEP,
THE FREQUENCY OF TESTING MAY BE VARIED TO MATCH THE WATER USE.
3. IN THE EVENT THE PW, PURIFIED WATER OR WFI DISTRIBUTION SYSTEM IS MONITORED CONTINUOUSLY BY
VALIDATED IN-LINE CONTROLS, SAMPLING AND TESTING FOR BACTERIAL ENDOTOXINS AND
MICROORGANISMS (AS APPLICABLE) MAY BE SUSPENDED FOR INTERVALS (SUCH AS WEEKENDS) OF UP TO
3 DAYS, PROVIDED THAT THE WATER IS NOT USED FOR PRODUCTION, IS CONTINUOUSLY RECIRCULATING
THROUGH THE DISTRIBUTION SYSTEM, AND ALL NORMAL OPERATING RANGES (NOR) ARE MAINTAINED.
4. FOLLOWING A WATER SYSTEM SHUTDOWN THAT EXCEEDS A VALIDATED TIME INTERVAL, ACTION MUST BE
TAKEN TO ENSURE ADEQUATE WATER QUALITY. SELECTED SAMPLES REPRESENTATIVE OF THE WATER
QUALITY, INCLUDING THE WORST CASE SYSTEM LOCATION AT A MINIMUM, SHALL BE COLLECTED AND
TESTED. ALL TEST RESULTS SHALL BE REVIEWED AND APPROVED BEFORE ANY PRODUCTS MANUFACTURED
USING THE WATER ARE RELEASED.

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 SAMPLING METHOD
• WATER SAMPLES AT POINTS OF USE SHALL BE COLLECTED IN A MANNER CONSISTENT WITH
MANUFACTURING PRACTICES INCLUDING, AND NOT LIMITED TO, THE FOLLOWING:
1. FLUSHING OF SAMPLE PORTS SHALL BE THE SAME AS FOR MANUFACTURING USE OF THE
WATER AT CORRESPONDING USE POINTS
2. WHERE SANITIZATION OF OUTSIDE SURFACES OF SAMPLE PORTS IS PERFORMED PRIOR
TO COLLECTING A SAMPLE (E.G., WIPEDOWN WITH A STERILE* ALCOHOL WIPE)
3. A STUDY SHALL BE PERFORMED TO DEMONSTRATE THAT THE SANITIZATION PROCESS
DOES NOT INHIBIT MICROBIAL RECOVERY, UNLESS THE SAMPLING PROCEDURE INCLUDES
SPECIFIC MEASURES TO NEUTRALIZE OR REMOVE THE SANITIZER
4. IF A HOSE IS USED TO TRANSFER THE WATER FOR USE IN MANUFACTURING, SAMPLING
SHALL BE PERFORMED THROUGH THE SAME OR AN EQUIVALENT HOSE.
5. IF SAMPLING THROUGH THE HOSE IS NOT POSSIBLE ON A ROUTINE BASIS, A
QUALIFICATION STUDY SHALL BE PERFORMED TO DEMONSTRATE THE EQUIVALENCE OF
SAMPLING WITH AND WITHOUT THE HOSE.

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 WATER SAMPLES

• WATER SAMPLES FOR MICROBIOLOGICAL TESTS SHALL BE COLLECTED IN

STERILE CONTAINERS USING A TECHNIQUE DESIGNED TO MINIMIZE
MICROBIAL CONTAMINATION OF THE SAMPLES.

• MICROBIOLOGICAL TESTING SHALL BE CONDUCTED AS SOON AS

POSSIBLE AFTER COLLECTION. IF SAMPLES CANNOT BE PROCESSED WITHIN
8 HOURS OF SAMPLE COLLECTION, THE SAMPLES SHALL BE REFRIGERATED
AT A TEMPERATURE OF 2 TO 8O C.

• THE TIME BETWEEN COLLECTION AND TESTING SHALL BE RECORDED AND

SHALL NOT EXCEED 24 HOURS.
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 SAMPLING POINTS
• WHERE SAMPLE PORTS CANNOT BE LOCATED IN CLOSE
PROXIMITY TO THE WATER USE POINT (E.G., WITHIN A METER),
DOCUMENTED RATIONALE SHALL BE PROVIDED TO JUSTIFY THE
SAMPLE LOCATIONS.

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Varadharaj. Vijayakumar
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