Total organic carbon (TOC) is an indirect measure of organic molecules present in pharmaceutical waters measured as carbon. Organic molecules are introduced into the water from the source water, from purification and distribution system materials, from biofilm growing in the system, and from the packaging of sterile and nonsterile waters.
TOC also can be used as a process control attribute to monitor the performance of unit operations comprising the purification and distribution system. A TOC measurement is not a replacement test for endotoxin or microbiological control. Although there can be a qualitative relationship between a food source (TOC) and microbiological activity, there is no direct numerical correlation.
Instrumentation requirements
A number of acceptable methods exist for analyzing TOC. Apparatuses commonly used to determine TOC in water for pharmaceutical use have in common the objective of oxidizing the organic molecules in the water to produce carbon dioxide followed by the measurement of the amount of carbon dioxide produced. Then the amount of carbon dioxide produced is determined and used to calculate the organic carbon concentration in the water.
Several companies manufacture analyzers for measuring carbonaceous material in liquid samples. The most appropriate system should be selected based on consideration of the types of samples to be analyzed, the expected concentration range, and the forms of carbon to be measured.
No specific analyzer is recommended as superior. If the technique of chemical oxidation is used, the laboratory must be certain that the instrument is capable of achieving good carbon recoveries in samples containing particulates.
Reagent water
Use water with a TOC level of NMT 0.10 mg/L. ASTM Type II water can also be used. [Note: A conductivity requirement may be necessary to ensure method reliability.]
System suitability solution
Dissolve an accurately weighed quantity of USP 1,4-Benzoquinone RS in Reagent water to obtain a solution with a concentration of 0.75 mg/L (0.50 mg/L of carbon).
Standard solution
Unless otherwise directed in the individual monograph, dissolve an accurately weighed quantity of USP Sucrose RS in the Reagent water to obtain a solution with a concentration of 1.19 mg/L of sucrose (0.50 mg/L of carbon). [NOTE: This standard is not required by some instruments.]
Reagent water control
Use a suitable quantity of Reagent water obtained at the same time as those used in the preparations of the Standard solution and the System suitability solution.
Water sample
Obtain an on-line or off-line sample that suitably reflects the quality of water used.
Other control solutions
Prepare appropriate reagent blank solutions or other specified solutions needed for establishing the apparatus baseline or for calibration adjustments following the manufacturer’s instructions, and run the appropriate blanks to zero the instrument, if necessary.
Limit response
Measure the TOC of the Reagent water control in the instrument, and record the response (rw). Also measure the TOC of the Standard solution in the instrument, and record the response (rS). Calculate the corrected Standard solution response, which is also the Limit response (rL), for the contribution from the Reagent water, by subtracting the Reagent water control response from the Standard solution response:
rL = rS − rW
Where,
- rS = instrument response to the Standard solution
- rW = instrument response to the Reagent water control. The Limit response (rL) of 0.50 mg/L of carbon will be equal to this corrected Standard solution response.
Procedure
Measure the TOC of the Water sample and record the response (rU). The Water sample meets the requirements if rU is NMT rL. This method can be performed using on-line or off-line instrumentation that meets the Instrumentation requirements.
What is the total organic carbon (TOC) limit for Purified Water and Water for Injection?
There is a "target limit response" of 500 µg of Carbon/L. The true limit is the response of the TOC measurement system to a 500 µg Carbon/L (prepared from sucrose) solution, Rs, corrected for the response to reagent water, Rw. This limit is equal to Rs – Rw. The actual number will vary based upon your reference standard solution, your equipment, background carbon, etc.
Reference: USP-NF 〈643〉
