<643> Total Organic Carbon

As of June 2021

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1. In643TOC, with respect to the preparation of the prescribed concentrations of sucrose and 1,4-benzoquinone standard solutions, how do I prepare the solutions if I do not have a balance that can weigh these small masses?
  • If you do not have a balance to accurately weigh the low mass, prepare a solution with a higher concentration that provides the correct solution accuracy.  Then perform an analytical dilution to the desired concentration  for executing the test method.  
  • If preparing a concentrated solution to dilute, be aware of the solubility of the reference standard to ensure that the solid will completely dissolve in the concentrated solution.
2. How accurately do I have to prepare 643 TOC standard and system suitability solution concentrations for testing Bulk Water?
  • Preparation of the reference solutions must be performed to achieve the accuracy as indicated by the significant digits in the test method, that is, 0.50 mg/L of carbon
  • The solution should be prepared to an accuracy of +/- 0.005 mg/L of carbon
  • Use a combination of appropriate analytical balances and volumetric glassware to achieve the solution accuracy.
3. In 643 TOC, Sterile Water, for containers greater than 100 mL, if the result is between 8.00 – 12.00 mg/L of carbon, the chapter says that any component that is contributing 0.20 mg/L of carbon or higher must be identified, quantified, and have their safety profiles evaluated. How can this be accomplished?

Organic extractable components from the packaging that contribute to the TOC profile of the sterile packaged water should have been identified, quantified, and evaluated for safety/toxicity during packaging development activities in order for the packaging to have been approved by FDA.  The methodologies used at that time could be the basis for any identification, quantification, and safety/toxicity studies needed for showing current compliance of sterile water product batches with their respective USP monographs. Additional guidance is available in General Chapters <661> and its sub-chapters, <1663> and <1664>.

If unknown organic impurities are also present, these will have to be evaluated using analytical methods most suitable for the determination.

Note Some factors that may cause high TOC can include the packaging system components and packaging process controls. The composition/concentrations of the specific packaging components used in the packaging of the water under investigation may be subtly different than what was originally qualified (e.g., resin differences from alternate suppliers). Also, the controls associated with the packaging/fabrication process (e.g., adhesives and mold release compounds) may have changed since original packaging approval resulting in unknown organic impurities.

4. Does the “Nominal Container Volume” as stated in 643 refer to the volume the container is intended to hold or the volume it is actually filled with?

The “Nominal Container Volume,” as stated in <643>, refers to the intended that the container is intended to hold.

If a container is intended to hold 5 mL and has an actual fill of 3 mL or a fill of 5.2 mL (to accommodate extractable volume), the Nominal Container Volume is considered 5 mL, and L1 is 32…  

If a container is intended to hold 10 mL and has an actual fill of 5 mL, the Nominal Container Volume is considered 10 mL, and L1 is 24