TOC Analysis Moving from Laboratory Testing to On-line Analysis

ABSTRACT
TOC Analysis
Moving from Laboratory Testing to On-line Analysis
TOC Analysis – Moving from laboratory to on-line monitoring.
March 2008 by Hach Ultra
Written By: Tony Harrison
Hach Ultra
tharrison@hachultra.com +44 (0) 7764 933 992
The Pharmacopoeias recommend that the starting material used to manufacture Purified Water (PW) and
Water for Injection (WFI) is water intended for human consumption as laid down by the competent
authority, such as the Environmental protection Agency (EPA) or World Health Organisation (WHO).
Target levels for the presence of Total Organic Carbon (TOC) contamination for both PW and WFI are set
at

LABORATORY WIDE-RANGING MEMBRANE CONDUCTIVITY TOC ANALYSERS
Laboratory-based TOC analysers utilise membrane conductivity (MC) with a CO2 permeable membrane
and two conductivity cells to measure conductivity before and after oxidation of the organic material.
Typically, the TOC analyser will have up to three conductivity probes; one for reporting conductivity and
two to make the before- and after-oxidation measurements.
MC technology was developed to provide a lab-based general purpose TOC analyser capable of
measuring TOC in a wide range of water types. Interference from other salts and chemicals present in
non-GMP waters is avoided as they cannot pass through the membrane, allowing the MC analyser to only
report increases in conductivity from the evolved CO2 from the oxidised TOC. However, they are a flowthrough
design and full oxidation the TOC is rarely achieved. Instead factors are used to extrapolate the
TOC from the slight changes in conductivity as the TOC is partially oxidised on it’s way through the
analyser.
This technology does not have a stable calibration and, if used for on-line analysis, is affected by
temperature, pressure and flow rate changes in the PW or WFI system. Also, the CO2 transfer rate
through the membrane is dependant on the pH and temperature of the water system. Slight drift in the
calibration of the multiple conductivity cells used can also contribute to inaccurate TOC analysis. In fact,
when this technology is used in the laboratory, a calibration check is frequently recommended for each
batch of TOC samples run to ensure that the analyser calibration has not drifted.
TOC Analysis – Moving from laboratory to on-line monitoring.
March 2008 by Hach Ultra
Figure 1: Lab-based Membrane Conductivity TOC Analysis
ON-LINE DIRECT CONDUCTOMETRIC-BASED TOC ANALYSERS
Direct Conductometric (DC) based TOC analysers, such as the Anatel PAT700, utilise a single
conductivity meter to measure the increased conductivity of a water aliquot after all the organic material in
the aliquot has been completely oxidised to carbon dioxide (CO2) using ultra-violet light.
Because the water treatment system creating PW and WFI is designed to GMP-compliant quality water,
there must be no potentially interfering contaminants present, so the membrane technology is not an
advantage and, being much more stable and robust in design than membrane flow-through TOC
analysers, these DC TOC analysers are not affected by the temperature, pressure and flow changes
expected on a typical PW or WFI system.
As shown in Figure 2 below, the WFI or PW aliquot is trapped in the analysis cell by valves, the oxidising
UV lamp is turned on and the organic materials are fully oxidised. The difference in conductivity created by
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the CO2 evolved through the oxidisation process is directly proportional to the amount of TOC present in
the aliquot. The analysis cycle typically takes around 3 minutes on PW and WFI, allowing the DC TOC
analyser to report TOC levels every 3 minutes.
TOC Analysis – Moving from laboratory to on-line monitoring.
March 2008 by Hach Ultra
Figure 2: On-line Direct Conductometric TOC Analysis
DC TOC analyzers are based on the assumption that the only conductive species generated during UV
oxidation is CO2. The amount of CO2 measured is directly proportional to TOC in the water sample.
MONITORING THE UV LAMP
Both laboratory and on-line TOC analysers for pharmaceutical-grade waters utilise ultra-violet light to
oxidise the organic material in the water to CO2. As the UV lamp ages it produces less UV light and it is
not as effective at oxidising the organic material. With on-line direct conductometric TOC analysers, it is
important that the oxidation time is varied to ensure complete oxidation.
However, it is possible that all TOC analysers will report very low (typically

combined with a ‘main’ and ‘standby’ UV lamp arrangement, so that on detecting the ‘main’ UV lamp
failure, the analyser can automatically switch to the ‘standby’ UV lamp and continue to monitor on-line
TOC whilst raising an alarm so that the maintenance team can replace the failed UV lamp in a timely
manner.
VERIFYING ON-LINE TOC ANALYSERS
Unlike the membrane-based analysers used for laboratory TOC analysis the on-line TOC analyser must
be robust, have a stable calibration and be capable of consistent, repeatable analysis under varying
sample temperatures, pressure and flow-rates.
Figure 4: TOC analysers use temperature-compensated conductivity measurement
TOC analysers are basically temperature-compensated differential conductivity instruments using UV light
to oxidise the organic material to CO2 and utilising before-and-after-conductivity measurements as a
surrogate measurement for TOC. They must be able to accurately monitor the temperature of the sample
as it is analysed to ensure that the final conductivity measurement is compensated for temperature
change, otherwise the small change in conductivity caused by the CO2 evolved from the oxidised TOC will
be swamped by the change in conductivity due to the temperature change in the sample.
Hence it is important to verify:
a) the calibration of conductivity meter used to measure TOC
b) the calibration of the temperature compensation sensor
c) the TOC meter calibration against USP-traceable TOC standards
d) system suitability
e) the UV lamps
a) Verifying the calibration of the conductivity meter used to measure TOC
Guidance was given in USP30 regarding the calibration verification conductivity meters. This
was split into two parts: meter calibration and cell constant. Hach Ultra provides an SOP for carrying
these tests out on the Anatel PAT700 TOC analyser: SOP 700-4.
Meter calibration verification is made by disconnecting the measurement cell and replacing it with a
known-value NIST-traceable resistor. Cell constant is verified by running a certified conductivity
sample through the measurement cell.
TOC Analysis – Moving from laboratory to on-line monitoring.
March 2008 by Hach Ultra
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Figure 5: Verifying calibration of TOC conductivity meter using NIST-traceable resistor
Figure 6: Verifying calibration of TOC conductivity cell using certified conductivity standard
b) Verifying the calibration of the temperature compensation sensor
The TOC analyser is a temperature compensated differential conductivity meter, so it is critical to
verify the accuracy of the temperature sensor used in the TOC measurement. Hach Ultra provides an
SOP for carrying this test out on the Anatel PAT700 TOC analyser: SOP 643-4.
This verification is done by connecting a NIST- traceable calibrated external temperature instrument to
the water sample inlet of the TOC analyser and comparing the temperature reading on the external
instrument to that of the TOC analyser internal temperature sensor.
Figure 7: Verifying calibration of TOC analysis temperature compensation sensor using external instrument
TOC Analysis – Moving from laboratory to on-line monitoring.
March 2008 by Hach Ultra
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c) Verifying the TOC calibration against USP-traceable TOC standards
The GMP-critical on-line TOC analyser is used to demonstrate that the TOC level in the PW or WFI
water system is 85%

e) Verifying the UV lamp
Correct operation of the UV lamp is fundamental to the TOC analysis. Robust on-line TOC analysers
will measure the UV lamp output and have main and stand-by UV lamps to ensure 100% up-time
should one of the UV lamps fail. When UV lamps age, their UV output falls and TOC oxidation times
are extended. The on-line TOC analyser must be designed to monitor the oxidation process and
adjust it’s oxidation cycle time to allow for varying amounts of TOC and ageing UV lamps, otherwise
the TOC analyser will report incorrect TOC levels.
Either using an external UV meter, or using the analyser’s built-in diagnostics, verify that the main and
standby UV lamps are working correctly.
CONCLUSION
TOC Analysis – Moving from laboratory to on-line monitoring.
March 2008 by Hach Ultra
Figure 10: Verify the Main and Standby UV lamps are working correctly
When moving from laboratory-based TOC analysis to on-line TOC analysis, it is important to consider the
type of TOC analyser to be used. The complex design used in the wide-ranging membrane conductivity
lab-based TOC analyser is not suitable for un-manned, on-line TOC analysis for the following reasons:
Laboratory membrane-based TOC analysers:
• Calibration is not stable and frequent re-calibration is required
• Not possible to verify the calibration of the conductivity cells used to measure TOC
• Not possible to verify or validate the calibration of the temperature compensation sensors
• TOC result affected by flow rate changes caused by pressure fluctuations in PW or WFI system
• TOC result dependant on UV lamp age, i.e. it is a flow-through design and the water is exposed to
the oxidising UV lamp for a fixed period, so, as the lamp intensity decreases with age, the TOC
analyser will tend to under-report the TOC present in the water
Direct Conductometric TOC analysers are stable and robust and the Anatel PAT700 is specifically
designed to support compliance and allows verification and calibration to all the pharmacopoeial
requirements:
Direct Conductometric on-line TOC analysers:
• Calibration is stable and supports 6-monthly re-calibration intervals
• The calibration of the conductivity cell used to measure TOC can be verified
• The calibration of the temperature compensation sensor can be verified
• TOC result is not affected by flow rate changes caused by pressure fluctuations in PW or WFI
system (the Anatel takes a sample aliquot and fully oxidises the TOC content)
• TOC result is not dependant on the level of the UV lamp output, i.e. the water sample aliquot
exposure to the oxidising UV lamp is extended until all the TOC is fully oxidised. So, despite the
lamp intensity decreasing with age, the TOC analyser will always report the correct TOC present
in the water
• UV lamp monitoring and ‘main’ and ‘standby’ UV lamps to ensure that lamp failure is detected and
that the analyser provides 100% up-time using the ‘standby’ UV lamp whilst the maintenance
teams arrange the failed lamp replacement.
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