TOC and Conductivity for USP and EP Water Systems

TOC and Conductivityfor

USP and EP Water Systems

Content

1. Conductivity

2. TOC analysis

3. Validating a TOC analyzer

4. Introduction to the PAT700 combined TOC and Conductivity Analyzer

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

Conductivity

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+-

Conductivity Meter

MeasurementCell

Cl-Na+

Conductivity varies with temperatureC

ondu

ctiv

ity =

TO

C

Temperature

USP<645> 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. USP<645>:

Content

1. Conductivity

2. TOC analysis



On-line TOC analysis – principle of operation

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+-

Conductivity Meter

MeasurementCell

UVlamp

On-line TOC analysis – principle of operation

+-

+-

+-

+-

Conductivity Meter

UV

UV

Organic materialturned to CO2

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+-

On-line TOC analysis - Principle of Operation

Time

Con

duct

ivity

UV on

conductivity = TOC

Organics oxidised to CO2

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 Hach’s, End Point Detection method, strictly meets this requirement for online TOC analyzers

Dynamic End Point Detection

USP <643> Requirement: Instrument Must Completely Oxidize the Sample

Content

1. Conductivity

2. TOC analysis



Validating the TOC analyser

1. Validate that the instrument matches the URS2. Validate that installation is as per manufacturer3. Verify Calibration

TOC Conductivity Temperature sensor

4. System suitability5. Verify connections to remote systems6. Performance qualification

Calibration is stable Analyser works correctly

Tests to validate the analyser

1. Validate that the instrument matches the URS2. Validate that installation is as per manufacturer3. Verify Calibration




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

Week 1IQ, Commissioning

First 4 weeksCalibration stability, System suitability

6 monthly testing

Tests to validate the analyser

1. Verify that the instrument matches the URS2. Verify that installation is as per manufacturer3. Verify Calibration




TOC Calibration – factory & on site

0 Injected TOC 1000

0R

epor

ted

TOC

1000

Factory Calibration

TOC Calibration on site

500ppb

250ppb

750ppb

TOC

Water system TOC value – modern system = 30 to 70ppb

Certified traceable standards

Calibration – As Found, As Left

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

System suitability – USP<643> & EP2.2.44

System suitability calculation

Sucrose analysis result = 475ppb TOC

Benzoquinone analysis result = 485ppb TOC

Calculation = Sucrose = 475 = >85%<115%Benzoquinone 485

Verifying conductivity – USP<645>

1. Verify meter accuracy (+/- 0.1S)

2. Verify cell constant (+/-2%)

3. Verify temperature sensor (compensation)

Temperature sensor verification

Verifying conductivity – meter accuracy

Accuracy ofmeter


Disconnect measurement cell


Replace cell withNIST traceable

resistor

Meter = Resistor +/-0.1S

Verifying conductivity – cell constant

Function area and distance

Area

Distance

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

Verifying conductivity – cell constant

Content

1. Conductivity

2. TOC analysis



PAT700 TOC Analyzer with OASISTM

Onboard, Automated Standards Introduction System

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

PAT700 – Supports all test requirements

• USP <643> Total Organic Carbon

• USP <645> Conductivity

• USP <788> Water for Injection

• USP <789> Opthalmic Water

• EP 2.2.38 Conductivity

• EP 2.2.44 Total Organic Carbon

• JP <60>

• 21 CFR Part 11

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

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.


Grab-sample analysis

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 )


OOS sample capture and root-cause analysis support

OOS sample capture capability

1. Utilizes OASIS sample bay2. OOS triggers automatic collection of

two samples3. Re-tests 1 bottle to confirm OOS4. Saves one sample for analysis in

laboratory to support root-cause analysis


21 CFR data export

21 CFR Part11 Data Export

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


Clean-In-Place verification

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 user’s specific criteria• Either conductivity threshold• Or time based

After TOC analysis, reports results and return to idle mode

• 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

On-line Monitoring of CIPFinal Rinse Water Verification


Laboratory TOC analysis

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


Water loop monitoring and root-cause analysis support

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

Bracketing POU for On-line Release

Pure Steam

Generation

Distillation - WFI

Points-Of-Use (POUs)

Contamination

Source

?

Contamination

Source

?


12-month service and calibration intervals

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

Questions?

PAT700 TOC and Conductivity Analyzer

Documents

TOC and Conductivity for USP and EP Water Systems