A - 82

Appendix 1

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description of the determination conditions including

instrument model, calibrated temperature value, sampling
amount and granularity of the substance being examined,
atmosphere pressure, direction and rate of temperature
change and the sensitivity of instrument.
It is needed to point out that purity determination using Vant
Hoff equation is based on the assumption that impurity does
not lead to formation of solid solution. Application of the
equation in accurately measuring the purity is limited
especially when the substance being examined is
polymorphism or decomposes at fusion point.

R Determination of Total Organic

Carbon in Water for Pharmaceutical
Use
This method is used for the indirect monitor of organic
substances present in water for pharmaceutical use by
measure of Total organic carbon (TO C). TOC can also be
used as a process control attribute to monitor the
performance of unit operations comprising the purification
and distribution system.
The organic substances present in water for pharmaceutical
use are generally from water source, water supply system
including purification, storage and distribution, and the
velum growth in water system.
Usually use sucrose as the easily oxidizable substance, and
1 -4-benzoquinone as the substance which is oxidized with
difficulty.
Prepare the standards solutions according to the requirements
and determine their responses on the instrument to test the
oxidizable ability of the instrument and system suitability.
General requirements for apparatus A variety of different
methods is available for measure of TOC. Any method may
be used to measure TOC in water as long as it could meet the
following requirements
(1) Discriminate between the inorganic carbon, which may
be present in the water due to dissolved CO2 and
decomposition of bicarbonate, and the CO2 generated from
the oxidation of organic molecules in the sample.
(2) Comply with the requirements for system suitability test
(3) To be of adequate sensitivity (with a limit of detection of
0. 05 mg or less of carbon per litre).
This test method is performed either as an on-line test or as
an off-line laboratory test using a calibrated instrument. It is
convenient for the on-line test system to achieve the real-time
monitor and in-process control on water systemquite a few
problems such as contamination caused by sampling
process, sampling container or loss-controlled environmental
factors ( including vapor of organic substances), may arise
from the off-line test system. Whether an on-line test system
or off-line test system is adopted, it is depends on the watertreatment system or justified in a particular case since
batch-size quantity of the water was prepared using a
continuous manufacturing process.
Water for TOC determination
Use highly purified water
with a TOC level of not more than 0. 10 mg per L and a
conductivity of not more than 1. 0
cm1 at 25C. The
water used for standard and system suitability test solution
prepared should share the same container.
Preparation of standard solution

Sucrose stan dard solution

Unless otherwise specified, dissolve an accurately weighed

quantity of sucrose CRS, dried to constant weight at 105C
in water for TOC determination to produce a solution
containing 1. 20 mg per L (0. 50 mg of carbon per L).
1 4-benzoquinone standard solution
Unless otherwise
specified, dissolve an accurately weighed quantity of 1 4benzoquinone CRS in water for TOC determination to produce a
solution containing 0. 75 mg per L (0. 50 mg of carbon per L).
Test solution Off-line test system Extreme caution shall
be taken when collecting samples for TOC analysis . Water
samples can be easily contaminated during the process of
sampling and transportation* In order to ensure the trueness
of the measured result, collect the Test solution in a tight
container with minimal head space, and carry out the test as
rapidly as possible to minimize the impact of organic
contamination and absorbed carbon dioxide.
Glassware must be scrupulously cleaned to remove the
organic residue and rinsed with water for TOC
determination.
OnrLine test system Properly connect the water-production
system to the on-line detection devices for TOC
determination. Both sampling system and measurement
system must be adequately cleaned.
System suitability test
Test the water for TOC
determination, Sucrose standard solution and 1 4benzoquinone standard solution separately in the apparatus
and record the response. Calculate the percentage response
efficiency using the following expression

rss

rw X 100

Where rw is the response of water for TOC determination, rs

is the response of Sucrose standard solution and
is the
response of 1 4-benzoquinone standard solution.
The response efficiency is not less than 85% and not more
than 115 % .

Procedure

To a volume of the water for pharmaceutical

use, carry out the test as described in instrument standard
operation procedure, run the test and record the response
(ru). Unless otherwise specified the response of specimen
of water for pharmaceutical use (ru) is not more than rsrw
(0. 50 mg/L).
The method can be applied using on-line or off-line
instrumentation that has been previously calibrated and
verified by system suitability test. The measured quality
attributes of water by such on-line or off-line instrumentation
is closely correlated to the sampling location(s) in the water
system. The sampling location(s) must actually reflect the
quality of the water for pharmaceutical use.

M. S

Determination of Conductivity of
Water for Pharmaceutical Use
This method is used for the monitor of total amount of
electrolyte present in water for pharmaceutical use by
measure of water conductivity. Conductivity is a physical
quantity which represents a materials ability to conduct an
electric current. The conductivity of a solution is, by
definition the reciprocal of resistivity. The unit of
conductivity is S/cm (Siemens) or pS/crru
For purified water, to some extent, water molecules dissociate
into hydrogen ions and hydroxide ions, and the conductivity
could be detected irrespective of pure waters poorly ability to

Appendix V A -83
conduct electricity. Water conductivity is closely correlated to
the purity of water, the purer the water, the lower the
conductivity, and vice versa. Some atmospheric gases, such as
carbon dioxide, readily dissolve in water and interact to form
ions, which predictably affect conductivity. Water conductivity
is also affected by the presence of extraneous ions, which raises
the conductivity. Additionally, the water conductivity varies as
a function of pH and temperature.
Instrument specifications and operating parameters
Water conductivity must be measured accurately using
calibrated instrumentation. The conductivity cell contains 2
parallel electrodes which are generally protected by a glass
tube. Other types of cells may also be used. The frequency
of recalibration is a function of instrument design, degree of
use, etc. The cell constant can be verified directly by using
a solution of known conductivity, or indirectly by comparing
the instrument reading taken with the cell in question to
readings from a cell of known or certified cell constant The
conductivity cell constant must be known within 2% .
Each scale on the meter may require separate calibration prior
to use. The instrument must have a minimum resolution of
0 .1 f j.S / c m on the lowest range and the instrument accuracy
must be 0. 1 ^tS/cm.
Because temperature has a substantial impact on conductivity
readings, many instruments automatically correct the actual
reading to display the value theoretically. This temperature
compensation algorithm may not be accurate and is not applied
for the water conductivity. Conductivity values used in this
method are
nontemperatur^compensated
measurements.
Accuracy of the temperature measurement must be 2C .
Procedure
1. Purified Water
Determine the conductivity off-line or in-line and record the
temperature. The corresponding conductivity value at the
recorded temperature in Table 1 is the limit. The water to be
examined meets the requirements if the measured
conductivity is not greater than the value in Table 1. For
temperatures not listed in Table 1 calculate the maximal
permitted conductivity by interpolation between the next
lower and next higher data points in the table. If the
measured conductivity is not greater than the conductivity
requirements, the water to be examined meets the
requirements of the test for conductivity. If the measured
conductivity is greater than this value the water to be
examined does not meet the requirements of the test for
conductivity.
Table 1 Temperature and conductivity
requirements (purified water)
T emperature/C

Conductivity/pS cm' 1
2.4

0
10

3.6

20

4,3
5. 1

25
30
40

5.4
6

.5

50

7. 1

60

8 .1

70

9. 1

75

9.7

80

9.7

90
100

9.7
.2

10

Interpolation is given by the expression

K

Where

= ( { ) X (K- K
)+

Kq

is the corresponding conductivity limit at the

measured temperature
Ki is the corresponding conductivity limit at the next
higher temperature on the table 1
Ko is the corresponding conductivity limit at the next
lower temperature on the table 1
T is the measured temperature
Ti is the next higher temperature on the table 1 ;
Tz is the next lower temperature on the table 1.
k

2. Water for Injection

( 1 ) Determine the conductivity off-line or in-line. Using
Table 2 find the closest temperature value that is not
greater than the measured temperature. The corresponding
conductivity value is the limit at that temperature. If the
measured conductivity is not greater than the value in Table
2 the water to be examined meets the requirements of the
test for conductivity. If the conductivity is higher than the
value in Table 2 proceed with stage 2.
Ikble 2 Ttn^ierature and conductivity requirements
(water for injection)
T emperature/ C

C o n d u c tiv ity / cm' 1

0 .6

0 .8

10

0.9

15

1 .0

.1

20

25

1. 3

30

1.4

35

1.5

40

1.7

45

1 .8

50

1.9

55

60

2 .2

65

2.4

70

2.5

75

2.7

80

2.7

85

2.7

90

2.7

95

2.9

100

3. 1

.1

(2) Transfer a sufficient amount of the water to be examined

(100 ml or more) to a suitable container, and stir the test
sample. Adjust the temperature if necessary, and while
maintaining it at 25d=lC , begin vigorously agitating the test
sample while periodically observing the conductivity. When
the change in conductivity is less than 0. 1 jjB cm"1 per 5
minutes, note the conductivity. If the conductivity is not
greater than 2 . 1 pS cm'1 the water to be examined meets
the requirements of the test for conductivity. If the
conductivity is greater than 2. 1 pS cm"1 proceed with
stage 3.
(3) Perform this test within approximately 5 minutes of the
conductivity determination under stage 2 while maintaining
the sample temperature at 2 5 1C . Add a recently prepared

<

A - 84

Appendix

saturated solution of potassium chloride to the test sample

(0. 3 ml per 100 ml of the test sample) and determine the
pH ( Appendix YI H ) to the nearest 0 .1 pH unit Using
Table 3 determine the conductivity limit at the measured
pH value. If the measured conductivity under stage 2 is not
greater than the conductivity requirements for the pH
determined, the water to be examined meets the
requirements of the test for conductivity. If either the
measured conductivity is greater than this value or the pH is
outside the range of 5. 0-7. 0 the water to be examined does
not meet the requirements of the test for conductivity.

continue
pH

Conductivity/fxS crrf1

Table 3 pH and conductivity requirements (for atmosphere

__________ and temperature equilibrated samples)__________
pH

C o n d u c tiv ity / cm' 1

5.0

4.7

3. Sterile Water for Ii^jection

Use off-line equipment and maintain the sample temperature at
25C. The limit is maximum 25 pS cm1 for containers with a
nominal volume of 10 ml or lessthe limit is maximum 5 ^tS
cm"1 for containers with a nominal volume greater than 10 ml If
the measured conductivity is not greater than the conductivity
requirements, the water to be examined meets the requirements
of the test for conductivity. If the measured conductivity is
greater than the limit, the water to be examined does not meet
the requirements of the test for conductivity.
6.0

2.4