Achieving USP Compliance for PW and WFI Waters

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TOC and Conductivity for USP and EP Water Systems
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Content

1. Conductivity
2. TOC analysis
3. Validating a TOC analyzer
4. Introduction to the PAT700 combined TOC and
   Conductivity Analyzer

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Dissociation and Conductivity

• Conductivity measures ionic activity
• Ionic compounds dissociate into ions, then
  re-associate back into the compound
• E.g. Sodium Chloride (NaCl) made from Na and Cl-
• Add energy and the Na and Cl- split, or
  dissociate
• The ions then contribute to the conductivity of
  the water
• Some substances dissociate more readily and
  contribute more strongly to conductivity
• Different temperature compensation curves for
  different waters

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Conductivity
Conductivity Meter
Na
Cl-
Measurement Cell
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Conductivity varies with temperature
Conductivity TOC
Temperature
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USPlt645gt Conductivity Temperature

• Conductivity meters will report different results
  depending on
• The compounds present in the water
• The temperature compensation curve selected
• Hence pharmacopoeias call for un-compensated,
  e.g. USPlt645gt

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Content

1. Conductivity
2. TOC analysis
3. Validating a TOC analyzer
4. Introduction to the PAT700 combined TOC and
   Conductivity Analyzer

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On-line TOC analysis principle of operation
Conductivity Meter
Measurement Cell
UV lamp
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On-line TOC analysis principle of operation
Conductivity Meter
UV
UV
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On-line TOC analysis - Principle of Operation
Conductivity
Time
UV on
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Letter of the Law

• USP (till recently) share the objective of
  completely oxidizing the organic molecules in an
  aliquot of sample water to carbon dioxide
• EP states have in common the objective of
  completely oxidizing the organic molecules in
  the sample water to produce carbon dioxide
• Only Hachs, End Point Detection method, strictly
  meets this requirement for online TOC analyzers

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Dynamic End Point Detection
USP lt643gt Requirement Instrument Must
Completely Oxidize the Sample
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Content

1. Conductivity
2. TOC analysis
3. Validating a TOC analyzer
4. Introduction to the PAT700 combined TOC and
   Conductivity Analyzer

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Validating the TOC analyser

• Validate that the instrument matches the URS
• Validate that installation is as per manufacturer
• Verify Calibration
• TOC
• Conductivity
• Temperature sensor
• System suitability
• Verify connections to remote systems
• Performance qualification
• Calibration is stable
• Analyser works correctly

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Tests to validate the analyser

• Validate that the instrument matches the URS
• Validate that installation is as per manufacturer
• Verify Calibration
• TOC
• Conductivity
• Temperature sensor
• System suitability
• Verify connections to remote systems
• Performance qualification
• Calibration is stable
• Analyser works correctly

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Validation documents procedures

• Demonstrate URS requirements are met through,
  Commissioning, IQ and OQ
• PQ demonstrates that the analyzer is stable and
  can support required calibration and system
  suitability intervals

6 monthly testing
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Tests to validate the analyser

• Verify that the instrument matches the URS
• Verify that installation is as per manufacturer
• Verify Calibration
• TOC
• Conductivity
• Temperature sensor
• System suitability
• Verify connections to remote systems
• Performance qualification
• Calibration is stable
• Analyser works correctly

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TOC Calibration factory on site
Factory Calibration
0 Reported TOC 1000
0 Injected TOC 1000
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TOC Calibration on site
TOC
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Certified traceable standards
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Calibration As Found, As Left
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System Suitability Test Must Be Performed

• System Suitability is not calibration!
• System suitability is the process of validating
  whether your system (i.e. TOC analyzer) is
  acceptable for providing useful analytical data
  without any bias.
• This is typically done by
• Analyzing a material that is easy-to-oxidize
  (sucrose)
• Analyzing a material that is difficult-to-oxidize
  (1,4 - benzoquinone)
• Calculating the ratio of the responses

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System suitability USPlt643gt EP2.2.44
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System suitability calculation

• Sucrose analysis result 475ppb TOC

Benzoquinone analysis result 485ppb TOC
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Verifying conductivity USPlt645gt

1. Verify meter accuracy (/- 0.1mS)
2. Verify cell constant (/-2)
3. Verify temperature sensor (compensation)

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Temperature sensor verification
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Verifying conductivity meter accuracy
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Verifying conductivity meter accuracy
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Verifying conductivity meter accuracy
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Verifying conductivity cell constant

• Function area and distance

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Verifying conductivity cell constant

• Introduce certified conductivity standard
• /-2 of certified standard
• Cell constant known within /-2

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Content

1. Conductivity
2. TOC analysis
3. Validating a TOC analyzer
4. Introduction to the PAT700 combined TOC and
   Conductivity Analyzer

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PAT700 TOC Analyzer with OASISTM

• Onboard, Automated Standards Introduction System

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Introduction to the ANATEL PAT700

• On-line TOC analysis with complete sample
  oxidation
• OASISTM Onboard, Automated Standards
  Introduction System
• Calibration and system-suitability test SOP
  built-in via color touch-screen
• Individual 4-20mA outputs for TOC, temperature
  and conductivity
• Main and standby auto-switching UV lamps with UV
  Detect technology
• IP 56 stainless-steel enclosure improves
  protection from water and particulates

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PAT700 Supports all test requirements

• USP lt643gt Total Organic Carbon
• USP lt645gt Conductivity
• USP lt788gt Water for Injection
• USP lt789gt Opthalmic Water
• EP 2.2.38 Conductivity
• EP 2.2.44 Total Organic Carbon
• JP lt60gt
• 21 CFR Part 11

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OASISTM Technology

• Saves time and delivers improved confidence in
  quality
• All bottles for a test installed at once and
  tests automated
• Information about each standard stored in RFID
  tag on the bottle
• contents, concentration, certified value, lot
  number, expiration date
• (Manual data entry possible for customer prepared
  standards)
• Analyzer voids bottle following test
• OASIS can be used for grab sample analysis

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Non-Hach Standards Warning Message

• If the user selects No, then the test is
  cancelled and the user is placed back at the Run
  Standards selection screen. 
• If the user selects Yes, then the user is
  prompted to enter all of the bottle information
  manually and the test is allowed to continue as
  if the bottle did not have an RFID tag at all.

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PAT700 TOC Analyzer with OASISTM

• Grab-sample analysis

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Grab Sample Analysis

• Utilizes OASIS sample bay
• Up to 4 grab sample bottles at a time
• Grab Sample Bottle ID nine character alphanumeric
  
• (ex. PW POU 01 )

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PAT700 TOC Analyzer with OASISTM

• OOS sample capture and root-cause analysis support

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OOS sample capture capability

1. Utilizes OASIS sample bay
2. OOS triggers automatic collection of two samples
3. Re-tests 1 bottle to confirm OOS
4. Saves one sample for analysis in laboratory to
   support root-cause analysis

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PAT700 TOC Analyzer with OASISTM

• 21 CFR data export

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21 CFR Part11 Data Export

• TOC Dataview PC Software
• Allows the viewing of encrypted data
• Allows decrypted data to be saved
• Encrypted file exported as filename.hef
• Read-only .pdf for record retention
• .txt files to load into LIMS database

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PAT700 TOC Analyzer with OASISTM

• Clean-In-Place verification

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On-line Monitoring of CIPFinal Rinse Water
Verification

• Conductivity can be used for detecting acid wash
  residues
• TOC can be used as broad-spectrum test to detect
  presence of drug material residues
• Unit programmed to meet users specific criteria
• Either conductivity threshold
• Or time based
• After TOC analysis, reports results and return to
  idle mode

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On-line Monitoring of CIPFinal Rinse Water
Verification

• Automated Mode (plc controlled)
• Unit idle until called for
• TOC analysis triggered via
• Digital input, or
• Serial command, or
• Modbus over Ethernet
• Reports results and return to idle mode

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PAT700 TOC Analyzer with OASISTM

• Laboratory TOC analysis

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PAT700 with auto-sampler

• Autosampler for laboratory use can load up to 36
  vials
• e.g. point-of-use and rinse water
  samples.(0-2000ppb)
• Provides a laboratory TOC analyzer without
  reagents or carrier gas

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PAT700 TOC Analyzer with OASISTM

• Water loop monitoring and root-cause analysis
  support

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Dual-stream option PAT700

• Two inputs
• One on the PW/WFI loop start, one on the return
• Brackets loop quality
• Helps root-cause investigation to find
  contamination source, e.g. feed-water or
  point-of-use

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Bracketing POU for On-line Release
Contamination Source ?
Points-Of-Use (POUs)
Contamination Source ?
Pure Steam Generation
Distillation - WFI
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PAT700 TOC Analyzer with OASISTM

• 12-month service and calibration intervals

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UV DetectTM Diagnostics

• Direct measurement of UV source performance
• Diagnosis of UV status
• Fast, real-time lamp feedback
• On-line Verified after every TOC analysis
• Off-line Can be conducted in diagnostic
  mode after lamp replacement
• Detects rouge contamination
• Provides confidence for on-line water release
• Standby UV lamp automatically switched on if main
  lamp fails avoids gaps in analysis data
• More reliable than simple hours-of-operation
  counters
• Reduces cost-of-ownership analyzer can support
  12-monthly calibration and service intervals

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Questions?

• PAT700 TOC and Conductivity Analyzer