NewsPharmaceutical 11

THORNTON Leading Pure Water Analytics

System Suitability Test is CompliantWith International Pharmacopoeia RegulationsDetermination of TOC (total organic carbon) in water for pharmaceutical

applications is regulated by the different pharmacopoeias for specific

water qualities. The easy and straightforward System Suitability Test

(SST) of THORNTON ensures compliance with all these regulations.

Relevance of the SSTTOC analysis in pharmaceutical-grade water is used for quality control purposes and is intended to detect organic con-taminants.

The TOC valueThe TOC value itself is an overall pa-rameter; in other words, it makes no state-ment about which organic contaminants are present (qualitative statement) but rather how much organic contaminant material is present (quantitative state-ment), and is expressed as μg/L C or ppb C. In principle, every TOC analyzer for pharmaceutical-grade water operates on the principle of oxidation of the organic content to CO2 and determination of the CO2. Neither the oxidation nor the method of determination is specified. Because dif-

ferent organic substances have different degrees of ease of oxidizability, however, the pharmacopoeias specify a system suit-ability test that demonstrates that sub-stances that are easy to oxidize as well as those that are difficult to oxidize are de-termined with sufficient accuracy.

Norms and interpretationsOn the one hand there are slight differ-ences between the individual Standards and on the other hand there is a need for clarification as to how the measurement results in the SST are to be interpreted, and which TOC tolerance limits to use.

Purified WaterPerspectives in Pure Water Analytics

■ For system suitability, then, the response (so-called) is calculated using the following formula:

■ The SST is deemed to give a conform-ing result if the Response is in the range of 100 ±15 %.

Example (a) rw = 22 ppb rs = 515 ppb rss = 495 ppb Response = 95.9 %. (SST conforming)

Example (b) rw = 26 ppb rs = 355 ppb rss = 334 ppb Response = 93.6 % (SST also conforming)

Although the measurements in Example (b) do not comply with the target value of 500 ppb C, the SST is still deemed to give a conforming result. Accordingly, the

2 METTLER TOLEDO Pharmaceutical PW News 11

Publisher / Production Mettler-Toledo AG

Process Analytics

Im Hackacker 15

CH-8902 Urdorf

Switzerland

IllustrationsChrist Osmotron, CH

Subject to technical changes.

© Mettler-Toledo AG 07/08

Printed in Switzerland.

phar m aceutical requirements are satis-fied. These low measurement values are mainly attributable to the inherent insta-bility of the SST solutions. THORNTON therefore always prepares fresh solutions shortly before the scheduled testing.

USP <643> and EP 2.2.44These two standards apply to TOC deter-mination for the American and European markets. They are fairly similar, but there are still several differences with regard to limit values and areas of application. As described in Example (b), the USP pro-vides for a maximum allowable TOC con-tent (ru) based on a difference value of the measurements (normalized value), ru = rs – rw. In other words, the American standard generates a variable limit value, so that, when the measured value differs from the nominal value, the limit value is reduced for quality assurance reasons. The European standard does not take this into consideration and specifies a fixed limit value of 500 ppb C. In current water systems for pharmaceutical applications

Measuring the TOC and performing the SSTThe following are required:■ Measurement using a calibrated

instrument. ■ The limit of detection must be

50 ppb C or lower.■ Proper performance of the SST using

an easily oxidized substance (sucrose), and using a difficult-to-oxidize substance (p-benzoquinone).

■ A standard solution, comprising sucrose (cane sugar), containing 500 ppb C, is used. This provides the measurement rs.

■ A reference solution, comprising p-benzoquinone, also containing 500 ppb C, is used. This provides the measurement rss.

■ The reagent water used to prepare the sucrose and p-benzoquine solution is also subjected to measurement. The resulting blank value, rw, should not exceed 100 ppb C.

Transmitter 770MAX.

Sensor 5000TOC.

rss – rw Response = 3 100 % rs – rw

■ A complete solution: The 770MAX provides a complete

platform for pharmaceutical-grade water analysis.■ Freshly prepared SST solutions■ Straightforward and easy to carry

out SST

Read more about it!

USP <643> EP 2.2.44 JP XVLimit value ru ≤ rs – rw ru ≤ 500 ppb C Limit value ≤ 500 ppb C Action level (in-line) ≤ 300 ppb C Action level (off-line) ≤ 400 ppb CArea of application WFI: required WFI: required PW: required HPW: required PW: Optional; alternative wet-chemical test for oxidizable substances

3METTLER TOLEDO Pharmaceutical PW News 11

■ The fastest TOC determination for purified water: The measurement is available in

about 1 minute.■ The only really on-line TOC determi-

nation: Avoids batch processing (with analysis

times of between 7 and 15 minutes); instead, continuous measurement.

■ Low maintenance overhead: No moving parts, no chemicals, no

membranes. All that is required is UV lamp replacement 23 per year.■ Fast start-up: Automatic recognition of the analyzer

and automatic configuration, thanks to THORNTON Smart Sensor Technol-ogy.

the TOC content is generally < 10 ppb C; that is, substantially below the required limit values, and thus even SST results as described in Example (b) provide ade-quate safety. The differences in the two standards are summarized in the table.

www.mt.com/770max

In addition to the tolerance limit of 500 ppb C, the Japanese pharmacopoeia (JP) recommends 2 Action Levels for the off-line and on-line TOC determination. On-line determination of the TOC is cur-rently not required by the U.S. and Euro-pean standards, but the benefits of on-line determination are obvious.

THORNTON TOC analysis – requirements satisfiedThe THORNTON 5000TOC sensor in com-bination with the multi-parameter multi-channel 700MAX transmitter is a high-performance system for TOC determina-tion in pharmaceutical-grade water and satisfies the requirements of the pharma-ceutical standards. It is characterized by the following features:

WFI: water for injection (aqua ad iniectabilia)HPW: highly purified water (aqua valde purificata)PW: purified water (aqua purificata)

International regulation of water quality and purityAchieving a specific level of water purity is essential in adhering with local regula-tory compliance standards. According to the recently published white paper from Mettler-Toledo Thornton:

“Improving water system performance: A continuous TOC measurement technol-ogy to enhance real-time process con-trol”,

the global monitoring of Total Organic Carbon (TOC) is mandatory as specified in the United States Pharmacopoeia (USP <643>), European Pharmacopeia (EP 2.2.44), and the Japanese Pharmaco-poeia’s monographs.

4METTLER TOLEDO Pharmaceutical PW News 113

Requirements for a TOC sensorA TOC sensor is a tool used to determine changes in the overall organics, and it has no specificity. The TOC sensor must how-ever, respond rapidly, be functional and stay on-line. This allows the pharmaceu-tical water to be produced and released with confidence without costly repercus-sions.

Mettler-Toledo Thornton double measurement solutionMettler-Toledo Thornton has developed the on-line TOC sensor 5000TOC based on high-intensity ultraviolet oxidation of a continuously flowing sample. The mea-surement is based on a pre-oxidation background conductivity measurement followed by flow of the sample through an UV oxidation chamber where organics are converted to carbon dioxide. A second conductivity measurement after the oxi-dation chamber determines any change in conductivity. The difference between the two conductivity measurements correlates with the TOC content of the sample.

Advantages of on-line testing■ Fast and real-time continuous on-line

TOC measurement to rapidly detect organic contaminants

■ Simple installation, operation-mini-mal maintenance which eliminates downtime

■ No reagents for reduced operation costs

■ Process engineered design■ Meets USP, EP & JP requirements■ Single solution provider for USP puri-

fied water and water for injection■ PAT initiative compliance for RTR of

purified water

Highly Reliable TOC Measurement as Requested by the USP RegulationsAccurate measurement of water quality is critical. The THORNTON

5000TOC fulfills all specifications as requested in the different pharma-

copoeias and guarantees fast and real-time monitoring.

5000

TOC

On-

Line

Tes

ting

THORNTON 770MAX at a glanceThe Multiparameter Analyzer /Transmit-ter with Smart Sensor Technology allows monitoring six channels of conductivity, resistivity, pH, ORP, dissolved oxygen, ozone, TOC, flow, temperature, pressure, and level.

Important features and benefits■ Due to its high versatility concurrent

monitoring of as many as six individ-ual sensors is possible and it transmits analog and digital data to system con-trollers and data acquisition systems.

■ It accepts input from eight sensor-types from which it computes values in any of 35 different units. This extensive variety is supported by a multi-line scrolling display.

■ The convenient and compact design simplifies specification, installation, start-up, calibration, operation and maintenance. It includes Smart Sensors for automated start-up, plug-in connectors for all inputs and out-puts, and universal power supply.

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Real-time testing with THORNTON 5000TOC and 770MAXReal-time release, continuous flow TOC sensors – such as the 5000TOC – provide a rapid response to an excursion with an opportunity in real-time to respond to and divert contaminated water. This al-lows closer control of the entire water pu-rification process through the under-standing of the UPW system characteris-tics. It also ensures that end users are receiving reliable high-quality water for the various uses in production. Detection of organic contamination is critical in our industry in achieving the purest water possible. The Mettler-Toledo Thornton 5000TOC and 770MAX platform ensures analytical accuracy, fast response and reliability, and can help determine – in real-time – if organics are being reduced in your system.

THORNTON 5000TOC at a glanceThe 5000TOC Sensor uses Smart sensor technology to interface with the 770MAX Multiparameter Analyzer Transmitter. The sensor uses proven ultraviolet oxida-tion with differential conductivity to ef-fectively determine TOC concentrations.

Important features and benefits■ Minimal installation and set-up time■ Continuous flow design for rapid TOC

response ■ Minimized maintenance as no gases

or reagents have to be handled, stored or replaced

■ Meets USP <643>, <645> and EP 2.2.44 requirements

■ Easy and economical integration into water purification make-up and distribution systems

■ Two TOC measurement points can be accommodated with one 770MAX instrument to manage performance of various unit processes with water purification systems.

THORNTON TOC SST – advantages at a glance ■ Easy to carry out■ Always freshly prepared

solutions■ Quick start-up■ The lowest cost per TOC

measurement point

Read more about it!To read the full text of this white paper, please visit:

Other readings on the importance of Con-ductivity measurements in Pure Water applications can be found under:

www.mt.com/thornton

www.mt.com/pro-realtime

Visit for more informationMettler-Toledo AGProcess AnalyticsIm Hackacker 15CH-8902 UrdorfSwitzerland

www.mt.com/pro

The catalog offers comprehensive overview on product fea-tures and specifications, benefits and recommended application areas, order details and much more for process analytics measurement solutions.

The product catalog covers complete measuring solutions for the parameters:■ pH■ Dissolved oxygen and O2 in gases■ Ozone■ Dissolved CO2

■ Conductivity■ Turbidity ■ TOC■ Flow

The featured product range includes:■ Electrodes / sensors■ Housings■ Process connections■ Transmitters / analyzers■ Cleaning and Calibration systems■ Cables■ Accessories

Order your copy of this useful desk tool today!

Process Analytics Product CatalogNew Edition 08 / 09 AvailableGet an overview of the latest INGOLD and THORNTON products available

for your process application with the new product catalog 08 / 09.