SOP for Total Organic Carbon (TOC) Analysis in Pharma

In pharmaceutical manufacturing, water is the most widely used ingredient. Ensuring its purity is not just a best practice—it is a regulatory mandate. Total Organic Carbon (TOC) analysis is the primary method used to monitor organic impurities in Purified Water (PW) and Water for Injection (WFI).

This article explores why TOC monitoring is critical, the science behind how analyzers work, and a step-by-step guide to standard calibration.

The Importance of TOC in Pharmaceutical Water Systems

Organic matter enters water systems through source water decay, purification materials, and distribution pipelines. Maintaining low TOC levels is essential for several reasons:

Microbial Control: High TOC levels provide a "food source" for bacteria. There is a direct correlation between TOC concentrations and the levels of endotoxins and microbes.
Biofilm Prevention: Sustaining low TOC helps inhibit the development of biofilms on pipeline walls, which are notoriously difficult to remove once established.
Regulatory Compliance: The USP, EP, and JP pharmacopoeias all recognize TOC as a required test for pharmaceutical-grade water.
Cleaning Validation: Beyond water testing, TOC is used in Clean-in-Place (CIP) procedures to ensure no cross-contamination exists between different drug product runs.

How a TOC Analyzer Works: The Differential Conductivity Principle

Most modern TOC analyzers, such as the Thornton 550, determine organic carbon levels by measuring differential conductivity.

The Process Flow

Initial Measurement: The sample enters the analyzer and passes through Sensor (1), which measures the initial conductivity and temperature.
UV Oxidation: The water enters an oxidation chamber where it is exposed to high-intensity 185 nm ultraviolet (UV) radiation. This breaks down organic molecules, oxidizing them into Carbon Dioxide ( $CO_2$ ).
Final Measurement: The $CO_2$ causes an increase in the water's conductivity. Sensor (2) measures this new value.
Calculation: The microprocessor calculates the difference between the initial and final conductivity. This change is directly proportional to the concentration of organic impurities in the water.

The measurement is continuous, typically flowing at 20 ml/min, allowing for a rapid response (under one minute) to any system disturbances.

Step-by-Step TOC Calibration Procedure

To maintain accuracy, TOC analyzers require regular calibration—typically quarterly. Below is the technical procedure for preparing standards and executing calibration.

1. Standard Preparation

Mother Solution (1000 ppm): Accurately weigh 0.2125 g of Potassium Hydrogen Phthalate (KHP) and dissolve in 100 ml of zero ppb water.
Working Solution (10 ppm): Dilute 1 ml of the Mother Solution into 100 ml of zero ppb water.
Calibration Points: * Zero Standard: Use zero ppb water (blank).

250 ppb: Dilute 10 ppm solution by a factor of 40.
500 ppb: Dilute 10 ppm solution by a factor of 20.
1000 ppb: Dilute 10 ppm solution by a factor of 10.

2. Software Configuration

Open the analyzer software, go to the File menu, and select New > Calibration Curve.
Select NPOC (Non-Purgeable Organic Carbon) as the analysis type.
Enter the "Multiple Injection" setting and browse to name your calibration file.
Add Calibration Points: Enter points from maximum to minimum (1000 ppb down to 0 ppb).
Click Finish to create the file.

3. Running the Calibration

Insert the created calibration file into the Sample Table.
Place the intake tube into the corresponding standard solutions when prompted.
Click START on the toolbar. The instrument will analyze each standard sequentially.
Verification: Record the standard area and calculate the Linearity Coefficient ( $R^2$ ). A value close to 1.0 indicates a successful, linear calibration.