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á643ñ TOTAL ORGANIC CARBON

INTRODUCTION
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.
A number of acceptable methods exist for analyzing TOC. This chapter does not endorse, limit, or prevent any technologies
from being used, but this chapter provides guidance on how to qualify these analytical technologies as well as how to interpret
instrument results for use as a limit test.
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.
All technologies must discriminate between the inorganic carbon, which may be present in the water from sources such as
dissolved carbon dioxide and bicarbonate, and the carbon dioxide generated from the oxidation of organic molecules in the
sample. The discrimination may be accomplished either by determining the inorganic carbon and subtracting it from the
total carbon (the sum of organic carbon and inorganic carbon), or by purging inorganic carbon from the sample before
oxidation. Although purging may entrain volatile organic molecules, such purgeable organic carbon is present in negligible

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quantities in water for pharmaceutical use.

Change to read:
PROCEDURES
1. Bulk Water

of Pure Steam.
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The following sections apply to tests for bulk Purified Water, Water for Injection, Water for Hemodialysis, and the condensate

1.1 Instrumentation requirements: This test method is performed either as an on-line test or as an off-line laboratory
test using a calibrated instrument. The suitability of the instrument must be periodically demonstrated as described
below. In addition, it must have a manufacturer’s specified limit of detection of 0.05 mg/L (0.05 ppm) or lower of
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carbon.
When testing water for quality control purposes, ensure that the instrument and its data are under appropriate control
and that the sampling approaches and locations of both on-line and off-line measurements are representative of the
quality of the water used. The water purification process, distribution, and use should be considered when selecting
either on-line or off-line measurement.
1.2 Reagent water: Use water with a TOC level of NMT 0.10 mg/L. [NOTE—A conductivity requirement may be necessary
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to ensure method reliability.]

1.3 Container preparation: Organic contamination of labware and sample containers results in higher TOC values.
Therefore, use labware and containers that have been scrupulously cleaned of organic residues. Any method that is
effective in removing organic matter can be used (see Cleaning Glass Apparatus á1051ñ). Use Reagent water (section
1.2) for the final rinse.
1.4 System suitability solution: Dissolve an accurately weighed quantity of USP 1,4-Benzoquinone RS in Reagent water
(section 1.2) to obtain a solution with a concentration of 0.75 mg/L (0.50 mg/L of carbon).
1.5 Standard solution: Unless otherwise directed in the individual monograph, dissolve an accurately weighed quantity
of USP Sucrose RS in the Reagent water (section 1.2) to obtain a solution with a concentration of 1.19 mg/L of sucrose
(0.50 mg/L of carbon).
1.6 Reagent water control: Use a suitable quantity of Reagent water (section 1.2) obtained at the same time as those
used in the preparations of the Standard solution (section 1.5) and the System suitability solution (section 1.4).
1.7 Water sample: Obtain an on-line or off-line sample that suitably reflects the quality of water used.
1.8 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.
1.9 Limit response: Measure the TOC of the Reagent water control (section 1.6) in the instrument, and record the
response (rw). Also measure the TOC of the Standard solution (section 1.5) 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 (section 1.2), by subtracting the Reagent water control response from the Standard solution response:

rL = rS − rW

rS = instrument response to the Standard solution (section 1.5)

rW = instrument response to the Reagent water control (section 1.6)

The Limit response (rL) of 0.50 mg/L of carbon will be equal to this corrected Standard solution response.
1.10 System suitability: Measure the TOC of the System suitability solution (section 1.4) in the instrument, and record
the response (rSS). Calculate the corrected System suitability solution response (rC) by subtracting the Reagent water
control response from the System suitability solution response:

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rC = rSS − rW

rSS = instrument response to the System suitability solution (section 1.4)

rW = instrument response to the Reagent water control (section 1.6)

Calculate the percent response efficiency (rE):

rE = 100 × ▲▲ (ERR 1-Sep-2021)(rC / rL)

rC = corrected instrument response to the System suitability solution (section 1.4)

rL = corrected instrument response to the Standard solution (section 1.5) (also known as the Limit response)

The TOC measuring system is suitable if the percent response efficiency (rE) is NLT 85% and NMT 115%. The suitability
of the instrument must be periodically demonstrated.
1.11 Procedure: Measure the TOC of the Water sample (section 1.7) 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 (section 1.1).
2. Sterile Water
The following sections apply to tests for Sterile Water for Injection, Sterile Purified Water, Sterile Water for Irrigation, Sterile
Water for Inhalation, and any other monographs that specify this section. The sterile waters are derived from
Purified Water or Water for Injection, and therefore have been determined to be compliant with the Bulk Water (section
1) requirements before being stored and sterilized in the container.

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Follow the requirements for Container preparation (section 1.3) and Other control solutions (section 1.8). Prepare the
Standard solution (section 2.4) and the System suitability solution (section 2.3) that correspond to the Limit response
(section 2.7) for the volume of the container being tested as specified in Table 1 and as described in steps 2 and 4 in
Procedure (section 2.9).

Nominal Container
Volume (mL)
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Table 1. TOC Limit Based on Container Volume
Limit 1
(L1)
(mg/L of carbon)
Limit 2
(L2)a
(mg/L of carbon)
≤5 32.00 48.00
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>5 and ≤100 24.00 36.00

>100 8.00 12.00

a Limit 2 concentrations are utilized to determine the system suitability requirements for the container volume being tested.
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2.1 Instrument requirements: The suitability of the instrument must be periodically demonstrated as described below.
In addition, it must have a manufacturer’s specified limit of detection of 0.10 mg/L (0.10 ppm) or lower of carbon.
2.2 Reagent water: Use water with a TOC level of NMT 0.50 mg/L. [NOTE—See General Notices, 8.230.30 Water in a
Compendial Procedure. A conductivity requirement may be necessary in order to ensure method reliability.]
2.3 System suitability solution: /Dissolve an accurately weighed quantity of USP 1,4-Benzoquinone RS in Reagent water
(section 2.2) to obtain a solution with a concentration that corresponds to the container volume being tested, as
specified in Table 2:

Table 2. System Suitability Solution Based on Container Volume

Nominal Container Volume 1,4-Benzoquinone Equivalent Carbon Concentration
(mL) (mg/L) (mg/L of carbon)
≤5 72.00 48.00

>5 and ≤100 54.00 36.00

>100 18.00 12.00

2.4 Standard solution: Unless otherwise directed in the individual monograph, dissolve an accurately weighed quantity
of USP Sucrose RS in the Reagent water (section 2.2) to obtain a solution with a concentration that corresponds to the
Standard solution (section 2.4), measured for the container volume being tested, as specified in Table 3:

Table 3. Standard Solution Based on Container Volume

Limit 1 Limit 2
(L1) (L2)

Equivalent Carbon Concen- Equivalent Carbon Concen-

Nominal Container Volume Sucrose Concentration tration Sucrose Concentration tration
(mL) (mg/L) (mg/L of carbon) (mg/L) (mg/L of carbon)
≤5 76.00 32.00 114.00 48.00
>5 and ≤100 57.00 24.00 85.50 36.00

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Table 3. Standard Solution Based on Container Volume (continued)

Limit 1 Limit 2
(L1) (L2)

Equivalent Carbon Concen- Equivalent Carbon Concen-

Nominal Container Volume Sucrose Concentration tration Sucrose Concentration tration
(mL) (mg/L) (mg/L of carbon) (mg/L) (mg/L of carbon)
>100 19.00 8.00 28.50 12.00

2.5 Reagent water control: Use a suitable quantity of Reagent water (section 2.2) obtained at the same time as those
used in the preparations of the Standard solution and the System suitability solution (section 2.3).
2.6 Water sample: Obtain water samples that suitably reflect the quality of the sterile water batch being tested.
[NOTE—See Container preparation (section 1.3).] Before opening the water packages to remove water samples for
analysis, vigorously agitate the packages to homogenize any TOC residues that may be present in packages. For small
packages, several packages may be required in order to collect a sufficient water volume for analysis. Otherwise test
water samples individually.
2.7 Limit response: Measure the TOC of the Reagent water control (section 2.5) and record the response (rW). Also measure
the TOC of the Standard solution (section 2.4) prepared at concentrations corresponding to the appropriate Limit 1,
and, if required for step 4 in Procedure (section 2.9), Limit 2 values from Table 1 for the container volume being tested.
The values in this table are the TOC limits based on container volume. Finally, record the instrument response to each
of the Standard solutions (section 2.4) for Limit 1 (rS1) and, if required, Limit 2 (rS2) from Table 1.
Calculate the corrected instrument response to the Standard solutions prepared at the Limit 1 (rL1) or Limit 2 (rL2)

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concentrations, as appropriate, by subtracting the Reagent water control response (rW) from the Limit 1 Standard
solution response (rS1) and, if required, the Limit 2 Standard solution response (rS2):

rL1 = rS1 − rW
ci and if required:

rL2 = rS2 − rW

rS1 = instrument response to the Limit 1 Standard solution

rS2 = instrument response to the Limit 2 Standard solution
rW = instrument response to the Reagent water control
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2.8 System suitability: Prepare the Standard solution (section 2.4) at the TOC concentrations corresponding to the Limit
2 in Table 3 for the container volume being tested. Prepare the System suitability solution (section 2.3) according to
Table 2 for the container volume being tested. Measure the TOC of the Reagent water control (section 2.5) in the
instrument, and record the response (rW). Measure the TOC of the Standard solution (section 2.4), and record the
response (rS). Calculate the corrected Standard solution response (rS − rW), by subtracting the Reagent water control
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response (rW) from the Standard solution response (rS). Measure the TOC of the System suitability solution (section 2.3)
in the instrument, and record the response (rSS). Calculate the corrected System suitability solution response (rSS − rW)
by subtracting the Reagent water control response (rW) from the System suitability solution response (rSS) (section 2.3).
Calculate the percent response efficiency (rE):

rE = 100 × [(rSS − rW)/(rS − rW)]

rSS = instrument response to the System suitability solution

rW = instrument response to the Reagent water control
rS = instrument response to the Standard solution

The system is suitable if the percent response efficiency is NLT 85% and NMT 115%. The suitability of the instrument
must be periodically demonstrated.
2.9 Procedure
1. Measure the TOC of the Water sample (section 2.6) and record the response (rU).
2. Compare the rU to the corrected instrument response (rL1) for Limit 1 [see Limit Response (section 2.7)] for the
appropriate nominal container volume.
3. If rU is NMT rL1, then the Water sample (section 2.6) meets the requirements and the test is completed.
4. If rU is greater than rL1, then compare rU from step 1 to rL2 for the appropriate nominal container volume.
5. If rU is greater than rL2, then the Water sample does not meet the requirements and the test is completed.
6. If rU is greater than rL1 but NMT rL2, then use suitable analytical procedures appropriate for the intended use
to identify and quantify each individual organic impurity exceeding a concentration of 0.20 mg/L of carbon.
7. If there are no individual impurities that exceed 0.20 mg/L of carbon, then the Water sample (section 2.6)
meets requirements and the test is completed.
8. If there are individual impurities that exceed 0.20 mg/L of carbon, then evaluate them for safety at the
concentrations found in this testing.

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9. If the evaluation of the organic impurities is deemed safe, then the Water sample (section 2.6) meets the
requirements and the test is completed.
10. If the evaluation of the organic impurities is deemed to impact patient safety, then the Water sample (section
2.6) does not meet the requirements and the test is completed.
ADDITIONAL REQUIREMENTS
• USP REFERENCE STANDARDS á11ñ
USP 1,4-Benzoquinone RS
USP Sucrose RS

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