Reprinted from

PHARMACEUTICAL ENGINEERING

quality systems

THE OFFICIAL TECHNICAL MAGAZINE OF ISPE

JULY/AUGUST 2014, VOL 34, NO 4

TOC Measurement Methods

Copyright ISPE 2014

www.PharmaceuticalEngineering.org

Innovations in UV Oxidation Direct

Conductivity TOC Measurement to
Improve Accuracy and Precision
by Roger Schmid and Randy Turner
This article presents innovations to improve the accuracy and reliability of UV
oxidation direct conductivity TOC measurement methods.

otal Organic Carbon or TOC is the carbon whose origin is organic in nature.
It can originate from naturally occurring organic acids, such as tannic acid,
bacteria, and abrasion of valves. The
measurement of TOC is critical to the
pharmaceutical industry because various regulatory bodies have established
limits for TOC in Water for Injection
(WFI) and other uses of water in pharmaceuticals. The main
regulatory guidelines are incorporated in the following:
1. USP<643>, Total Organic Carbon, United States Pharmacopoeia 36-NF 31, U.S. Pharmacopeial Convention
Inc., Rockville, Md. (2013).
2. USP<645>, Water Conductivity, United States Pharmacopoeia 36-NF 31, U.S. Pharmacopeial Convention Inc.,
Rockville, Md. (2013).
3. USP<1231>, Water for Pharmaceutical Purposes,
United States Pharmacopoeia 36-NF 31, U.S. Pharmacopeial Convention Inc., Rockville, Md. (2013).
4. EP 2.2.38, Conductivity, European Pharmacopoeia, vol.
7.0, Council of Europe, Strasbourg, France (2013).
5. EP 2.2.44, Total Organic Carbon in Water for Pharmaceutical Use, European Pharmacopoeia, vol. 7.0, Council
of Europe, Strasbourg, France (2013).
6. JP 4.5.2, Monitoring of TOC as the Indicator for Organic
Impurities, JP XVI.
To measure TOC, the organic molecules must be reduced to

inorganic carbon allowing quantitative measurement of the

resultant carbon dioxide CO2. The organic molecule can be
decomposed to inorganic carbon by thermal decomposition,
UltraViolet (UV)-persulfate oxidation, and direct UV oxidation. The following are common methods of TOC analysis:
1. Thermal decomposition with NDIR detection
2. UV-persulfate oxidation with NDIR detection
3. UV-persulfate oxidation with conductivity detection
4. Direct UV oxidation with conductivity detection
Each process is based on the oxidation of the organic carbon
that is present in the water and the subsequent measurement
of the carbon dioxide which results from the oxidation. These
methods all have advantages and disadvantages depending
on how the oxidation and measurements are technically carried out. Therefore, each application has to be first examined
as to which of the different methods is the most suitable.

Methods of TOC Analysis

Thermal Decomposition
With this process, the organic particles are destroyed by
high temperatures. In this way, the undissolved components
(suspended solids or wear debris) are also completely decomposed - Figure 1. This is a common method particularly
with a high TOC load (e.g., municipal sewage).

UV-Persulfate Oxidation with NDIR or

Conductivity Detection
The wet-chemical oxidation with UV light and persulfate is,

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TOC Measurement Methods

Figure 1. Schematic diagram of thermal decomposition.

Figure 2. Schematic diagram of UV-persulfate decomposition.

especially with purified water and ultrapure water applications, widely spread and accepted as the standard. A great
advantage of this method is the large operational range of
less than 1 part per billion (ppb) to more than 100 parts per
million (ppm) with high accuracy.

TC
Total Carbon
The sum of inorganic and organic carbon (TIC plus TOC),
the value of which is determined by the second sensor

Direct UV Oxidation

TOC
Total Organic Carbon
The component that originates from biological sources,
e.g., biofilm or cells

Direct UV oxidation is applied only in ultrapure water and

pharmaceutical applications where chemicals are not necessary. These instruments have been increasingly in use over
the last few years. This article demonstrates the possibilities
and limitations of modern TOC instruments by means of
concrete examples. Details of the characteristics of direct UV
on-line monitors will be presented to show the latest developments (e.g., functional test) which simplify daily routines
and ensure safety. All the above mentioned methods have
their particular advantages and disadvantages according to
the systems limitations. For this reason, it is important to
choose the instrument exactly for its application and environment.

Direct UV Oxidation with Conductivity

Detection
Why is direct UV oxidation often selected to monitor TOC in
the pharmaceutical industry? This method is fast and very
reliable. Chemicals are not necessary and the maintenance is
simple and easy which allows simple and compact analyzers.
After the first conductance measurement, the sample flows
into the UV-reactor. In this SWAN design, the water is
directly channelled over the surface of the UV lamp to the
second conductance measurement cell. The TOC concentration is calculated from the different values of the two sensors
- Figure 3.

TIC in ultra-pure water and pharmaceutical applications is

almost solely CO2 from atmospheric CO2. In most pharmaceutical production plants, the TIC is greater than the TOC.
As with every other system, the direct UV method also has
its limitations.
1. Limited range
a. Conductivity < 2 microsiemens per centimeter (< 2
S/cm) at 20C
b. TOC < 1 parts per million (ppm)
2. Reproducibility of UV-oxidation
3. Thermal effects
4. Accuracy
To avoid the mentioned disadvantages, we focused on
achieving a complete oxidation by:

TOC = TC TIC
TIC
Total Inorganic Carbon
The component that originates from inorganic sources,
e.g., CO2
The values are determined by the first sensor

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Figure 3. Schematic diagram of direct UV oxidation.

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TOC Measurement Methods

1. Stabilization
of the thermal
conditions
2. Increase of
radiation flux
3. Optimization of
the sample flow
A few measures
and modifications had to be
developed to reach
this goal. All the
presented changes
had a huge effect
on the method presented below.

Stabilization
of the Thermal
Conditions
The direct UVmethod is strongly
Figure 4. Reactor with a heat exchanger.
influenced by
temperature effects. Due to the energy transfer from the UVlamp, the sample temperature will be increased up to 10C
from conductivity sensor 1 to 2. The conductivity has to be
compensated for this temperature difference. Unfortunately,
the compensation is only an approximation depending on
temperature and conductivity resulting in a potential error
in measurement. As a result of our research, the reactor is
fitted upstream with a heat exchanger where the outgoing
water warms the counter current incoming water. With this,
we can minimize the temperature difference between sensor
1 and sensor 2 to below 0.2C. Particularly, on samples with
low TOC values, this modification minimizes measurement

Figure 5. Intensity curve of a mercury low-pressure lamp.

errors. The achieved results are considerable stable and have

lower variabilitys than before - Figure 4.

Increasing Radiation Density during UVOxidation

The UV-lamps (Hg low pressure quartz bulb) employed,
have a narrow temperature band where they produce the
maximum energy output. This peak point is between 40C
and 50C. Figure 5 shows the summary spectrum (185 and
254 nm) of an Hg lamp. The 185 nm UV wavelength exhibits
a more pronounced impact by temperature.
From the Figure 5, the importance of keeping the temperature of the lamp within the optimal range is clear. Outside
influences (environmental temperatures, location) and the
sample water itself (changing sample temperatures) can lead
to lamp temperatures outside the optimal range.
The heat exchanger solution minimizes the difference
between the two conductivity sensors to less than 0.2C.
However, in order to maintain the temperature in the optimal range between 40C and 50C, further measures are
necessary. An additional heating cartridge or sample cooler
as seen in Figure 6 enable a target temperature of 42C to be
precisely sustained. Thus, the maximum radiation efficiency
is achieved, resulting in optimal and consistent oxidation.

Optimization
of the Sample
Flow Through
the UV Lamp
The aforementioned measures
already show a
substantial improvement to the
system. The full
potential is only

Figure 6. Reactor with heat exchanger and

a heating cartridge.

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realized in combination with an optimized sample flow. The

classic design of a UV lamp and the sample is flowed around
the light source. Divergence loss and reflection are practically unavoidable. The formation of deposits on the directly
radiated surface, which decreases radiation density, cannot
be fully eliminated in long running operations. This side
effect can only be avoided by establishing a direct contact
between the UV lamp and the sample.
Figure 7 demonstrates the sample flow in the newly engineered UV reactor. The sample flows directly along the lamp.
The furthest distance from the middle of the lamp is 8 mm
and the sample layer is only 0.5 mm thick. Divergence loss
and ozone production is prevented because of the enclosed
construction. This optimization leads to a distinct increase
of radiation density, resulting in complete oxidation of the
carbon compounds present in the sample. The UV lamp
forms a single unit with the reactor case. The entire reactor can be replaced in the case of a failure and is recyclable.
Maintenance is easier and faster.
Stable temperatures and a consistent, intense radiation
are the foundations for exact and reliable measurement
values. Equally important, however, is the compensation
method, i.e., how the measured values are converted to the
standard temperature.

Conductivity of the water before oxidation at the first sensor (COND 1) 0.6 S/cm at 42C
Conductivity of water after UV oxidation at the second
sensor (COND 2) 0.8S/cm at 42C
The absolute conductance of pure water void of CO2 at
42C is about 0.12 S/cm.

The Conductivity Measurement

Temperature Compensation

The calibration is performed with a 1 ppm solution. If the

results deviate more than expected from the target value,
certain requirements have not been fulfilled, the operating
parameters are wrongly adjusted, or the instrument has malfunctioned. This determination of TIC and TOC under the
conditions described is an absolute method. The extent of
a possible divergence is specified in the menu installation
and an adjustment cannot be made.

Stable temperature conditions are the basic principles of

accurate and reliable test results; however, the compensation method is equally important. This is how the measured
conductance is converted to a comparative temperature. The
conversion to a common reference temperature can be based
on different algorithms; however, these formulas are not
absolute. For this reason, SWAN uses two different compensation methods, depending on the chosen application range.

Carbon Dioxide (CO2) Model

Water for pharmaceutical applications can by definition

contain no salt. It can contain traces of organic carbon compounds (TOC) and dissolved carbon dioxide (TIC) from the
atmosphere. Atmospheric CO2 should be the only source of
TIC. Below is an actual example with rounded figures:

Figure 7. Cross section of a UV reactor.

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The difference in between the theoretically conductivity of

pure water (0.12 S/cm) and the conductivity at the first
sensor (0.6 S/cm), which in this example is 0.48 S/cm,
must therefore come from CO2. TIC can be calculated from
the definite correlation between conductivity and the carbon
dioxide concentration. The corresponding values for the
various temperatures are tabulated and stored in the instrument. The organic constituents in our example are converted
to CO2 by the UV lamp resulting in a conductivity of 0.8 S/
cm after oxidation at the second sensor. Consequently, the
value at sensor 2 is higher than sensor 1. The difference between the conductivity value at sensor 2 and sensor 1 (due to
the oxidation of organic carbon to form CO2 thereby increasing the conductivity) is converted to ppb TOC an algorithm.
[CONDUCTIVITY 2] [CONDUCTIVITY 1] = 0.2 S

Calibration

Linear Compensation
This method is meaningful when there is no clear correlation
between TOC content and conductivity.
With such applications, a TOC-conductivity ()-model
can be constructed by the production of calibration solutions which cover the concentration range of the relevant
components. The temperature dependency of the conductivity of the samples only needs to be taken in consideration
when the calibration and the online-monitoring are made
at different temperatures. The AMI line
TOC stabilizes the sample temperature,
not just with online-monitoring, but also
with a calibration at 42C to 43C. In
order to allow readings with deviating
temperatures, the conductivity values in
and out are converted to 25C.
A constant temperature performance
is assumed over the entire measurement
range with a linear compensation. This
value can be manually changed.

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TOC Measurement Methods

The calibration in linear mode occurs through the measurement of an exactly defined sample solution (Sucrose
1 ppm). Based on the measurement result, the instrument
calculates the effective slope, which it displays. From experience, the values are in the range of 0.15 to 0.3.

Pharmaceutical Application
Measurement Points
In modern WFI and Pure Water (PW) plants, most measurements are made at the points mentioned below:
Typically in pharmaceutical plants, it is after the distillation,
in the storage tank, at the entrance and exit of the loops and
of course at the point of use - Figure 8.

The Functional Check an Aide

Instruments that are installed in pharmaceutical applications must pass a System Suitability Test (SST) according to
the authoritative pharmacopeia (USP 643 / EP 2.2.24). The
specifications of the test solution in these monographs are
described in detail.
If the test is carried out in plants which produce according to the USP guidelines, the solutions have to be produced
with USP certified reagents. Due to the extreme dilution, the
storage life of these solutions is limited to only a few weeks.
An SST is the only possibility to check a TOC instrument in
praxis.

Figure 8. Possible installation in the pharmaceutical water preparations.

The prevailing UV lamps have a life expectancy of six

months in instruments with direct UV oxidation. Every lamp
exchange requires an SST, which means a minimum of two
tests a year. Many operators also use the certified SST solutions more often than the required validation interval, even
up to monthly checks. This involves considerable costs and
is logistically very time consuming.
The automatic functional test of the AMI line TOC can
effectively simplify this routine. The process is similar to
the established SST. Highly concentrated solutions (sucrose
and benzoquinone) are used, which last up to three months.
The solutions are diluted at the time of the test with sample
water by an integrated peristaltic pump. Both stock solutions
are measured one immediately after the other. Conclusions
can be made about the functions and the conditions of the
instrument by the degree of recovery. The basic function of
the instrument can be easily proved without intervention or
external modification. The operator has the ability to examine the instrument regularly online, reducing the number of
expensive and elaborate tests.
The functional test is activated manually or by a programmable timer. The applied solutions are not subject to pharmaceutical guidelines and can be produced by the operators
themselves. The substances can be purchased from the local

Figure 9. TOC analyzer.

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chemical distributor as long as they comply with the quality

requirements for an analysis.

Simple Grab Sample Testing

An extra benefit of the operating process is the possibility of
examining grab samples with the instrument. The sample is
drawn through the instrument by a peristaltic pump, regardless of whether it is an SST sample, a functional test or a
grab sample - Figure 9. Grab samples are easily connected
and can be measured immediately by the press of a button.
As long as the grab sample measurement mode is active,
the signal outpoints of the last value is held to avoid a false
alarm.
After the grab sample measurement mode is over, the
instrument is rinsed for a set time before the signal points
are released to active reporting.

Conclusion
The focus of the development of the TOC analyser concentrated on three areas:
The stabilizing thermal conditions
Increasing the radiation density
Optimizing the sample flow in the system
The technical solutions presented have verifiably improved
the precision and accuracy of direct UV oxidation. Moreover,
the exacting requirements of the pharmaceutical industry
with reference to the standards for calibration and verification were specifically taken into consideration during the
development.

Purified Water
Total Carbon
Total Inorganic Carbon
Total Organic Carbon
Ultra-Pure Water
Water For Injection

Definitions
Adjustment: set of operations carried out on a measuring
system so that it provides prescribed indications corresponding to given values of a quantity to be measured.
Note: adjustment of a measuring system should not be
confused with calibration, which is a prerequisite for adjustment.
Note: after an adjustment of a measuring system, the
measuring system must usually be recalibrated.
Calibration: operation that, under specified conditions,
in a first step, establishes a relation between the quantity
values with measurement uncertainties provided by mea-

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Validation: the documented act of demonstrating that a

procedure, process, and activity will consistently lead to the
expected results.
Verification: the process of checking that a product or
system meets specifications and that it fulfils its intended
purpose.

References
1. USP<643>, Total Organic Carbon, United States Pharmacopoeia 36-NF 31, U.S. Pharmacopeial Convention
Inc., Rockville, Md. (2013).
2. USP<645>, Water Conductivity, United States Pharmacopoeia 36-NF 31, U.S. Pharmacopeial Convention
Inc., Rockville, Md. (2013).
3. USP<1231>, Water for Pharmaceutical Purposes,
United States Pharmacopoeia 36-NF 31, U.S. Pharmacopeial Convention Inc., Rockville, Md. (2013).
4. EP 2.2.38, Conductivity, European Pharmacopoeia,
vol. 7.0, Council of Europe, Strasbourg, France (2013).

Acronyms
PW
TC
TIC
TOC
UPW
WFI

surement standards and corresponding indications with

associated measurement uncertainties and, in a second step
uses this information to establish a relation for obtaining a
measurement result from an indication.
Note: calibration should not be confused with adjustment
of a measuring system, often mistakenly called self-calibration or with verification of calibration.
Note: often, the first step alone in the above definition is
perceived as being calibration.

PHARMACEUTICAL ENGINEERING

5. EP 2.2.44, Total Organic Carbon in Water for Pharmaceutical Use, European Pharmacopoeia, vol. 7.0,
Council of Europe, Strasbourg, France (2013).
6. JP 4.5.2, Monitoring of TOC as the Indicator for Organic Impurities, JP XVI.

About the Authors

Roger Schmid began his employment
in various pharmaceutical companies in
Switzerland and after eight years joined
Mettler-Toledo. He was working in sales
and key account management specializing
in pharmaceutical and biotech industry
projects. In 2008, he moved to Australia as a product application specialist and subsequently joined Swan Analytical
Instruments, Switzerland in 2009. As a product manager,
he was responsible for the development process of the TOC
analyzer and associated instruments in the pharmaceutical

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TOC Measurement Methods

industry, and in 2010, he became the Industry Application

Manager for Swan as UPW and pharmaceutical product
lines. He can be contacted by email: [email protected].
Randy Turner was a power plant chemist
for Southern Company for 17 years and
corporate chemist supporting their fleet of
fossil plants for 16 years. He became the
Technical Director for Swan Analytical USA
in January 2012. He holds a BA in chemistry from the University of West Georgia. He has authored and
presented numerous papers on power plant chemistry at conferences and has authored or coauthored papers published in
industry journals. Turner was the chairman of EPRIs Cycle
Chemistry Program. He was awarded the EPRI Technology
Transfer Award in 2010 for research in corrosion product
transport monitoring and chemical cleaning of supercritical
units. He is a member and the first Vice Chair of the ASME
Power Plant and Environmental Chemistry Committee. He
is a member of the ASME Water Management Committee,
the International Properties of Water and Steam Power Cycle
Committee, AWWA, and WEF. He can be contacted by email:
[email protected].

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