THORNTON

Leading Pure Water Analytics

Application Note
The Use of TOC Measuring in
CIP and Cleaning Validation Applications
Background TOC (Total Organic Carbon) and conductivity are
Pharmaceutical manufacturing is one of the closely monitored as a means of ensuring proper
most strongly regulated industries in order to chemical qualities for these waters have been
protect patient safety. This is particularly true maintained throughout the manufacturing process.
in regards to the manufacture, use and testing The use of WFI, HPW, and PW in cleaning and
of Water for Injection (WFI), Pure Water (PW) validation of process equipment and process ves-
and Highly Purified Water (HPW). The United sels is common practice, and these waters, as well
States Pharmacopeia (USP) and European as the instrumentation used to test them, are
Pharmacopeia (EP) and all other pharmacopeias required to meet the USP Chapter <643> or EP
set strict guidelines for water quality (chemical 2.2.44 guidelines for TOC. The TOC limit for Pure
and microbiological impurities) and testequip- Water is 500 ppb at 25˚C. (Note: the Japanese
ment as used in pharmaceutical and biotech Pharmacopeia has specified a TOC limit of 400
manufacturing. ppb when measured offline and 300 ppb when
measured online for process control). See Table 1.
Table 1a - Pharmacopeia requirements for Purified Water

Attribute* USP 34 EP 6.6 JP 16

Production Method Suitable Process Suitable Process Distillation, ion-exchange,

UF, or combination
Source Water US, EU, Japan, WHO Human consumption JP water specification
drinking water
†
Total Aerobic (cfu/mL) 100 100 100

Conductivity 1.3 (3 stage) 5.1 (1 stage) 2.1 offline

‡
(µS/cm at 25°C)
TOC (mg/L) 0.5 0.5 (optional) 0.5

Nitrates (ppm) 0.2 Not detectable

††
Heavy Metals (ppm) 0.1 Not detectable

Oxidizable Substances <0.1 mL** 0.02 KMnO** < 0.10 mL 0.02 KMnO**
(/100 mL)
Note * : All tests are maximum, unless otherwise stated.
Note † : Microbiological testing is considered to be harmonized, with the exception noted that the EP test is written
into the Production section, and the USP test is contained in a non-compendial general information chapter
Note ‡ : Limits are temperature dependent
Note ** : Alternative to TOC
Note †† : Not required effective Jan 1, 2009 if WFI conductivity requirements are met
 Table 1b - Pharmacopeia requirements for Water For Injection (WFI)

Attribute* USP 34 EP 6.6 JP 16

Application Note

Production Method Distillation or suitable Distillation Distillation, RO with UF, from

process Purified Water
Source Water US, EU, Japan, WHO drink- Human consumption JP water specification
ing water
†
Total Aerobic (cfu/100 mL) - 10

Conductivity (µS/cm at 1.3 (3 stage) 1.3 (3 stage) 2.1 offline

‡
25°C)
TOC (mg/L) 0.5 0.5 0.5 (0.3 for control)

Bacterial Endotoxins 0.25 0.25 0.25

(EU/mL)

Note * : All tests are maximum, unless otherwise stated.

Note † : Microbiological testing is considered to be harmonized, with the exception noted that the EP test is written
into the Production section, and the USP test is contained in a non-compendial general information chapter
Note ‡ : Limits are temperature dependent

Use of TOC and conductivity in cleaning The current trend for the control and monitoring of TOC
validation applications and conductivity in typical CIP and other cleaning appli-
In pharmaceutical manufacturing, process vessels, cations is to flush the final WFI or PW rinse for a pre-
fermentation tanks, process piping and medicine determined amount of time, monitoring conductivity until
packaging machines and other equipment that come a specified water quality is reached. Once the water
in contact with the product must have a user defined quality is improved sufficiently, grab samples of the final
and validated cleaning method. Thorough cleaning rinse product are taken for time-consuming lab or batch
is required to prevent cross contamination between analysis of TOC concentration or other analysis such as
product batches as well as from microbial buildup HPLC. This not only causes significant downtime of
on vessel walls and equipment. Examples of clean- equipment, but also may introduce sample contamina-
ing processes include a rinse with WFI, HPW or PW, tion. Continuous online monitoring of TOC and conduc-
chemical cleaning Clean In Place (CIP) followed by tivity in real time during the final rinse phase of the
a WFI rinse or Steam in Place (SIP) cleaning. CIP, cleaning cycle, rather than grab or batch sample analy-
typically used for process vessels, uses an acid sis, is an enhanced strategy for monitoring the cleaning
rinse/spray followed by caustic treatment, and finally process of the final rinse cycle.
multiple WFI rinses.
By continuously monitoring the TOC and conductivity
This final use of WFI ensures that all chemicals used quality of the final rinse water, better control of the
to clean the vessel have been removed and that the process can be maintained, saving both time and water.
vessel can be put back online for production. In all The Thornton family of TOC and conductivity sensors
cases where a WFI or PW rinse is used, the vessel provides continuous online real-time monitoring, ensur-
or equipment can be considered “clean” when the ing that the CIP or cleaning cycle is determined by water
TOC and conductivity of the incoming water is the quality and not a pre-set time or number of rinse cycles,
same as that flushing out to drain. which may result in prolonged wasted cycles or improp-
er and incomplete cleaning, and thus non-compliance.
 Conclusion
TOC and conductivity have been process monitoring
points within the pharmaceutical industry for many
years. The ability to use the continuous online real-time
measurement technology of the Thornton TOC sensor for
cleaning validation and CIP applications can greatly
improve the efficiency of the process as well as reduce
equipment downtime, resulting in higher product yields.

In addition to continuous online monitoring of TOC and

conductivity to improve CIP and cleaning processes, val-
THORNTON 5000TOCe sensor and 770MAX transmitter
idation and calibration according to USP or EP require-
ments are essential in maintaining regulatory compli-
ance in pharmaceutical manufacturing. The Thornton
Meeting TOC and conductivity validation
5000TOCe sensor in conjunction with 770MAX transmit-
requirements for cleaning processes
ter meets the strict requirements of USP <643> and EP
Appropriate cleaning methods and validation
2.2.44 for TOC measurement. This reduces downtime
processes are defined by individual pharmaceutical
associated with excursions, maximizes efficiency, and
users for their specific equipment and in accordance
reduces cost associated with product loss, staffing and
with internal Good Manufacturing Practices (GMP).
equipment. System Suitability Testing as well as sensor
However, because the WFI or PW waters used in CIP
and transmitter calibration, key components of both
and cleaning applications come in contact with
mandates, can be conveniently performed in house. A
process equipment and process vessels, these
number of products such as Thornton pre-packaged
waters are required to meet USP standards for TOC
System Suitability standards, calibration kits and valida-
and conductivity measurements.
tion packages can reduce equipment maintenance labor
and downtime and help to ensure FDA compliance and
These TOC standards include a limit of detection
Good Manufacturing Practices.
of 0.05 mg Carbon/L (50 ppb), the ability to
calibrate the sensor and that the sensor meets a
System Suitability Test (SST). This System Suitability
Test challenges the TOC sensor with two standard
solutions -- 500 ppb Sucrose and 500 ppb
p-Benzoquinone -- and requires that the response
efficiency of these standards, adjusted for the TOC of
the water used to make these solutions, be between
85% and 115%.

The ability to quickly and easily perform the calibra-

tion and System Suitability Test in-house is an
important feature of any TOC sensor used in CIP and
cleaning processes, as it can further reduce costly
equipment down-time as well as allowing closer
control of internal validation practices. In instances
where low or no flow to the TOC sensor exists due to
gravity drainage of the process vessel or other
restrictions, the accessory Thornton Pump Module
can be used in conjunction with the TOC sensor to Thornton calibration/SST module with 5000TOCe sensor

provide constant delivery of the water sample to the

sensor to ensure accurate monitoring.
 www.mt.com/thornton
Visit for more information

Mettler-Toledo Thornton, Inc.

36 Middlesex Turnpike
Bedford, MA 01730 USA
Phone: +1-781-301-8600
Fax: +1-781-301-8701
Toll-Free: 1-800-510-PURE (US and Canada Only)
[email protected]

Subject to Technical Changes

© Mettler-Toledo Thornton, Inc.
AN-0130 Rev A 07/11