Oxidation Processes
Oxidation Processes
Oxidation Processes
PHARMACEUTICAL ENGINEERING
quality systems
www.PharmaceuticalEngineering.org
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
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quality systems
TOC Measurement Methods
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
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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PHARMACEUTICAL ENGINEERING
quality systems
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
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
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quality systems
TOC Measurement Methods
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.
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PHARMACEUTICAL ENGINEERING
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.
quality systems
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.
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TOC Measurement Methods
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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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
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.
quality systems
TOC Measurement Methods
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