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       Total Organic Carbon (TOC) determination is an indirect measure of organic substances present in water for pharmaceutical use. TOC determination can also be used to monitor the performance of various operations in the preparation of medicines.

      A variety of acceptable methods is available for determining TOC. Rather than prescribing a given method to be used, this appendix describes the procedures used to qualify the chosen method and the interpretation of results in limit tests. A standard solution is analyzed at suitable intervals, depending on the frequency of measurements; the solution is prepared with a substance that is expected to be easily oxidizable (for example, sucrose) at a concentration adjusted to give an instrument response corresponding to the TOC limit to be measured. The suitability of the system is determined by analysis of a solution prepared with a substance expected to be oxidizable with difficulty (for example, 1,4-benzoquinone).

      The various types of apparatus used to measure TOC in water for pharmaceutical use have in common the objective of completely oxidizing the organic molecules in the sample water to produce carbon dioxide followed by measurement of the amount of carbon dioxide produced, the result being used to calculate the carbon concentration in the water. 

      The apparatus used must discriminate between organic and inorganic carbon, the latter being present as carbonate. The discrimination may be effected either by measuring the inorganic carbon and subtracting it from the total carbon, or by purging inorganic carbon from the sample before oxidization. Purging may also entrain organic molecules, but such purgeable organic carbon is present in negligible quantities in water for pharmaceutical use.

      Apparatus Use a calibrated instrument installed either online or off-line. Verify the system suitability at suitable intervals as described below. The apparatus must have a limit of detection specified by the manufacturer of 0.05 mg or less of carbon per litre.

      Reagent water Use Purified Water complying with the following specifications:

      – conductivity: not more than 1.0 μS/cm at 25º,

      – total organic carbon: not more than 0.1 mg/l.

      Depending on the type of apparatus used, the content of heavy metals and copper may be critical. The manufacturer’s instructions should be followed.

      Glassware preparation Use glassware that has been scrupulously cleaned by a method that will remove organic matter. Use the reagent water for the final rinse of glassware.

      Standard solution Dissolve sucrose, previously dried at 105º for 3 hours in the reagent water to obtain a solution containing 1.19 mg of sucrose per litre (0.50 mg of carbon per litre).

      Test solution Using all due care to avoid contamination, collect water to be tested in a tightly closed container leaving minimal head-space. Examine the water with minimum delay to reduce contamination from the container and its closure.

      System suitability solution Dissolve 1,4-Benzoquinone in the reagent water to obtain a solution having a concentration of 0.75 mg of 1,4-benzoquinone per litre (0.50 mg of carbon per litre).

      Reagent water control Use the reagent water obtained at the same time as that used to prepare the standard solution and the system suitability solution. 

      Other control solutions Prepare suitable blank solutions or other solutions needed for establishing the baseline or for calibration adjustments following the manufacturer’s instructions; run the appropriate blanks to zero the instrument.

      System suitability Test the reagent water control in the apparatus, and record the response, r_w. Repeat the test using the standard solution, and record the response, r_S. Calculate the corrected standard solution response, which is also the limit response, by subtracting the reagent water control response from the response of the standard solution. The theoretical limit of 0.50 mg of carbon per litre is equal to the corrected standard solution response, r_S – r_w. Test the system suitability solution in the apparatus, and record the response, r_ss. Calculate the corrected system suitability solution response by subtracting the reagent water control response from the response of the system suitability solution, r_ss – r_w. Calculate the response efficiency for the System suitability solution by the formula:

      The system is suitable if the response efficiency is not less than 85 per cent and not more than 115 per cent of the theoretical response.

      Procedure Run the test solution and record the response (r_U). The test solution complies with the test if r_U is not more than r_S – r_w.

      The method can also be applied using on-line instrumentation that has been adequately calibrated and shown to have acceptable system suitability. The location of instrumentation must be chosen to ensure that the responses are representative of the water used.