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General Chapter 643

United States pharmacopoeia

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General Chapter 643

United States pharmacopoeia

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pramodyad5810
Copyright
© © All Rights Reserved
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Download as PDF, TXT or read online on Scribd
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Pharmacopeial Forum

Vol. 33(4) [July–Aug. 2007] 1


&
TOC measurement technologies should discriminate the
BRIEFING
inorganic carbon, which may be present in the water from
sources such as dissolved CO2 and bicarbonate, from any CO2
h643i Total Organic Carbon, USP 30 page 257. This chapter has
been modified in response to inquiries regarding the following that may be generated during the analysis of the organic
topics: (1) to address the relationship between TOC and microbi-
ological activity, (2) to provide guidance to the analyst on the components. In addition to other requirements listed below,
method, and (3) to provide emphasis on the allowance of on-line
measurements. the System Suitability test is the challenge to the TOC tech-
(PW: G. Ritchie) RTS—C52360 nology.&2S (USP31)

Change to read:
Change to read:
Total organic carbon (TOC) is an indirect measure of organic Apparatus Requirements—This test method is performed either
molecules present in pharmaceutical waters measured as carbon. as an on-line test or as an off-line laboratory test using a calibrated
Organic molecules are introduced into the water from the source instrument.
water, from purification and distribution system materials, and from
biofilm growing in the system. TOC can also be used as a process
&
On-line TOC measurements for bulk-produced waters such
control attribute to monitor the performance of unit operations
comprising the purification and distribution system. as Purified Water, Water for Injection, and Pure Steam
&
A TOC measurement is not a replacement test for endotoxin condensate have the advantage of providing real-time

or microbiological control. While there can be a qualitative measurements and opportunities for real-time process control

relationship between a food source (TOC) and microbiolog- and decisions, in addition to recording the TOC quality

ical activity, there is no direct numerical correlation. &2S (USP31) attribute for release of water to production. Due to the high
A number of acceptable methods exist for analyzing TOC. This
chapter does not limit or prevent alternative purity of these waters, off-line measurements of bulk waters
&
endorse, limit, or prevent any&2S (USP31)
have the disadvantage of being impacted adversely by the
technologies from being used, but
sampling method, sampling container, and uncontrollable
&
this chapter&2S (USP31)
provides guidance on how to qualify these analytical technologies environmental factors such as organic vapors. Because water
for use as well as guidance on how to interpret instrument results for
use as a limit test. The Standard Solution is a theoretically easy-to- production could be a batch operation or a continuous
oxidize solution that gives an instrument response at the attribute
limit. The analytical technology is qualified by challenging the operation, the nature of the water production should be
capability of the instrument using a theoretically difficult to oxidize
solution in the system suitability portion of the method. considered when determining if off-line or on-line measure-
Analytical technologies utilized to measure TOC share the
objective of completely oxidizing the organic molecules in an ment is to be used.&2S (USP31)
aliquot of sample water to carbon dioxide (CO2), measuring the The suitability of the apparatus must be periodically demonstrated as
resultant CO2 levels, and expressing this response as carbon described below. In addition, it must have a manufacturer’s specified
concentration. All technologies must discriminate between the limit of detection of 0.05 mg of carbon per L (0.05 ppm of carbon) or
inorganic carbon, which may be present in the water from sources lower.
such as dissolved CO2 and bicarbonate, and the CO2 generated from
the oxidation of organic molecules in the sample. Change to read:
Two general approaches are used to measure TOC. One approach
determines TOC by subtracting the measured inorganic carbon (IC)
from the measured total carbon (TC), which is the sum of organic Glassware Preparation—
carbon and inorganic carbon: &
Container Preparation—&2S (USP31)
TOC = TC – IC. Organic contamination of glassware
&
containers&2S (USP31)
The other approach first purges the IC from the sample before any results in higher TOC values. Therefore, use glassware and sample
carbon measurement is performed. However, this IC purging step
also purges some of the organic molecules, which can be retrapped, &
&2S (USP31)
oxidized to CO2, and quantitated as purgeable organic carbon (POC). containers that have been scrupulously cleaned of organic residues.
The remaining organic matter in the sample is also oxidized to CO2 Any method that is effective in removing organic matter can be used
and quantitated as nonpurgeable organic carbon (NPOC). In this (see Cleaning Glass Apparatus h1051i). Use Reagent Water for the
approach, TOC is the sum of POC and NPOC: final rinse.
TOC = POC + NPOC.
Change to read:
In pharmaceutical waters, the amount of POC is negligible and
can be discounted. Therefore, for the purpose of this methodology,
NPOC is equivalent to TOC.

# 2007 The United States Pharmacopeial Convention All Rights Reserved.


Pharmacopeial Forum
2 Vol. 33(4) [July–Aug. 2007]

Standard Solution—Unless otherwise directed in the individual


&
where rS is the instrument response to the Standard Solution;
monograph, dissolve in the Reagent Water an accurately weighed
quantity of USP Sucrose RS, to obtain a solution having rss is the instrument response to the System Suitability
a concentration of about
Solution; and rw is the instrument response to the Reagent
&
&2S (USP31)
1.2 mg of sucrose per L (0.50 mg of carbon per L). Water Control.&2S (USP31)
The system is suitable if the response efficiency is not less than 85%
and not more than 115% of the theoretical response.
Change to read:
Change to read:
Test Solution—[NOTE—Use extreme caution when obtaining
samples for TOC analysis. Water samples can be easily contaminated
during the process of sampling and transportation to a testing Procedure—Perform the test on the Test Solution, and record the
facility.] Collect the Test Solution in a tight container with minimal response, rU. The Test Solution meets the requirements if rU is not
head space, and test in a timely manner to minimize the impact of more than the limit response, rS – rw. This method also can be
organic contamination from the closure and container. performed alternatively
&
&2S (USP31)
using on-line
&
FOR OFF-LINE TESTING—Use caution when obtaining
samples for TOC analysis. Water samples can be easily
&
or off-line &2S (USP31)
instrumentation that has been appropriately calibrated, standardized,
and has demonstrated acceptable system suitability. The acceptabil-
contaminated during the process of sampling and transpor- ity of such on-line instrumentation for quality attribute testing is
dependent on its location(s) in the water system. These instrument
tation to a testing facility. Collect the Test Solution in a tight location(s) and responses must reflect the quality of the water used.
container with minimal head space, and test in a timely &
meets the Apparatus Requirements. For both on-line and off-
manner to minimize the impact of organic contamination line measurements, the suitability of instrumentation for
from the closure and container. quality control testing is also dependent on the sampling
FOR ON-LINE TESTING—Use caution when connecting the location(s) in the water system. The selected sampling
on-line TOC measurement system to the water production location(s) must reflect the quality of the water
system. The piping and measurement system may require used.&2S (USP31)
substantial time to rinse depending on many factors.&2S (USP31)

Change to read:

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.&2S (USP31)

Change to read:

System Suitability—Test the Reagent Water Control in the


apparatus, and record the response, rw. Repeat the test using the
Standard Solution, and record the response, rS. 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 L is equal to the corrected Standard Solution
response, rS – rw. Test the System Suitability Solution in the
apparatus, and record the response, rss. Calculate the corrected
System Suitability Solution response by subtracting the Reagent
Water Control response from the response of the System Suitability
Solution, rss – rw. Calculate the response efficiency for the System
Suitability Solution by the formula:
100[(rss – rw) / (rS – rw)]

# 2007 The United States Pharmacopeial Convention All Rights Reserved.

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