Principle and Calibration of TOC (Total Organic Carbon) Analyzer : Pharmaceutical Guidelines

Principle and Calibration of TOC (Total Organic Carbon) Analyzer

Learn how to calibrate the Total Organic Carbon Analyzer used to determine the organic carbon in Purified Water and Water for Injection.

Introduction of organic matter into water systems occurs not only from living organisms and from decaying matter in source water, but also from purification and distribution system materials. A relationship may exist between endotoxins, microbial growth, and the development of biofilms on pipeline walls and biofilm growth within pharmaceutical distribution systems. A correlation is believed to exist between TOC concentrations and the levels of endotoxins and microbes. Sustaining low TOC levels helps to control levels of endotoxins and microbes and thereby the development of biofilm growth. The United States Pharmacopoeia (USP), European Pharmacopoeia (EP) and Japanese Pharmacopoeia (JP) recognize TOC as a required test for purified water and water for injection (WFI). For this reason, TOC has found acceptance as a process control attribute in the pharma industry to monitor the performance of unit operations comprising water purification and distribution systems. As many of these pharma operations include the preparation of medicines, the U.S. Food and Drug Administration (FDA) enacts numerous regulations to protect the health of the public and ensure the product quality is maintained. To make sure there is no cross-contamination between product runs of different drugs, various cleaning procedures are performed. TOC concentration levels are used to track the success of these cleaning validation procedures especially clean-in-place (CIP).
TOC Analyzer measures Total Organic Carbon in pure and ultrapure water based on differential conductivity. This difference in conductivity is used to determine the amount of organic carbon present.

TOC Analyzer Flow Chart


The sample water enters the analyzer and passes through a pressure regulator, which controls sample pressure to downstream components. Here the sample splits into two flow paths, where a portion of the flow is directed to the by-pass streamline, where resistivity/conductivity and temperature are measured via Sensor (3). These values are represented on the LCD display. The other portion of the sample is directed through a second conductivity sensor, (1), measuring the sample conductivity prior to oxidation. Next, the sample enters the oxidation chamber. As the sample moves through the oxidation chamber, it is subjected to high intensity ultraviolet radiation at 185 nm, effectively oxidizing the sample to CO2.

After oxidation, the sample passes through a third conductivity sensor, (2), where the conductivity and temperature are measured again to determine the level of Total Organic Carbon (TOC). The microprocessor of the Thornton 550 TOC Analyzer uses the measured values of initial (1) and final (2) conductivity and temperature to determine the change in compensated conductivity, which is related to the concentration of organic impurity in the incoming water stream.

The measurement and sample flow are continuous; therefore, measurement update time is minimized, providing rapid response to any system disturbances. The oxidized sample stream passes through a flow meter, which has a fine flow-control adjustment, and then through the OXIDIZED SAMPLE OUTLET port. This effluent may be sent to waste or recycled. The operating flow rate is typically 20 ml/min, resulting in time in the oxidation chamber of less then one minute. The conductivity measurements are continuous; therefore, response time is directly related to the residence time of the sample in the oxidation chamber. Values of TOC, resistivity (or alternatively conductivity or uncompensated conductivity), and temperature are displayed on the LCD screen of the instrument. These values can also be printed or sent to a computer through RS-232 serial interface ports on the back panel of the instrument at a user-selectable time interval. The last 255 sets of values are stored in memory at the same time interval for viewing on the screen, or a designated number of these data lines can be printed on a demand basis. Other outputs include a continuous 4-20 mA self-powered analog output signal and two configurable potential-free alarm contacts. Refer to the specifications in the back of this manual for details regarding these outputs


1.0 Standard Preparation.
1.1 Weigh accurately 0.2125 gm of Potassium Hydrogen Phthalate and dissolve in 100 ml of zero ppb water, to get 1000ppm carbon concentration. Use this solution as mother solution.
1.2 Take 1 ml of (1000ppm sol.) in 100 ml of zero ppb water to get 10ppm sol.
2.0 Zero ppb Water (distilled water treat as a blank)
2.1 Zero water or blank water itself is the Zero Standard. Collect it in a 100 ml volumetric flask.
3.0 250 ppb Solution
3.1 From 10 ppm solution and set the dilution factor as 40.
4.0 500 ppb Solution
4.1 From 10 ppm solution and set the dilution factor as 20.
5.0 1000 ppb Solution
5.1 From 10 ppm solution and set the dilution factor as 10.
6.0 From the sample table window click on file menu select “New”. The new dialog box is displayed. Double click on “Calibration curve icon”.
7.0 Calibration curve wizard will be displayed. Select the dilution factor from standard solution option and click on “next”.
8.0 Select analysis as NPOC, and enter the default sample name & sample ID. Also select the “Multiple Injection” .Give the calibration file name by browsing and click OK. Click on “Next”.
9.0 Select the measurement parameters and click “Next”.
10.0 5 Calibration points list is displayed. In this page click on add and give the highest calibration point first. And give the “CAL” points from maximum to minimum by clicking “Add”. And then click “Next”.
11.0 In the last click on “Finish”.
12.0 Calibration file was created and now we have to insert it in the sample table.
13.0 Record the standard area and calculate the linearity coefficient.
14.0 Frequency of calibration – Quarterly in a year. Calibrate the system on due date within 6 days.

Inserting the Calibration File in the Sample Table

1. By placing cursor on the sample table, click on insert menu and select calibration curve.
2. Calibration curve file window will be displayed, select the created file name and click on “Open” button.
3. In the sample table row calibration standard will be inserted.
4. Now click on “START” button on the Tool Bar. Another window will be displayed, click on start.
5. Now instrument will analyze the standards, after completion of each standard a window will be displayed click on “Next” each time.

Ankur Choudhary is India's first professional pharmaceutical blogger, author and founder of Pharmaceutical Guidelines, a widely-read pharmaceutical blog since 2008. Sign-up for the free email updates for your daily dose of pharmaceutical tips.
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