WATER FOR INJECTIONS 8 Aqua ad iniectabile 9 Water for

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Reference: PA/PH/Exp. WAT/T (14) 7 ANP 1
NOTE ON THE MONOGRAPH 2
There have been ongoing discussions for many years as to whether there is a need to include non-distillation
technologies as a method for production of water for injections (WFI). The main concerns had been linked to
the microbiological safety of the water produced by membrane techniques. Following the survey issued by the
EDQM in March 2010 to gather data on the use of non-distillation technologies for producing WFI, as well as
the expert workshop organised by the EDQM in March 2011 (Water for Injections – Potential Use of Membrane
Systems for the Production), it was considered that sufficient evidence had been provided for the Ph. Eur.
Commission to recommend initiating discussions with stakeholders regarding the potential use of membrane
systems for the production of WFI. 3
A revision of the monograph is proposed to take into account current manufacturing practices using methods
other than distillation for producing water of injectable quality. The monograph revision is supported by the
evidence provided in the document Reverse osmosis in Ph. Eur. monograph Water for injections (0169),
published in Pharmeuropa (Useful information). 4
Production: the monograph has been revised to include, in addition to distillation, reverse osmosis coupled
with suitable techniques, for the production of WFI; a requirement for regular total organic carbon monitoring
has been added to emphasise further the specific test controls required in the Production section. 5
As a result of introducing non-distillation technologies into this monograph, the monograph Water, highly
purified (1927) will be made redundant and will be deleted from the Ph. Eur. 6
XXXX:0169 7
WATER FOR INJECTIONS 8
Aqua ad iniectabile 9
H2O 10
Mr 18.02 11
DEFINITION 12
Water for the preparation of medicines for parenteral administration when water is used as vehicle (water for
injections in bulk) and for dissolving or diluting substances or preparations for parenteral administration (sterilised
water for injections). 13
Water for injections in bulk 14
PRODUCTION 15
Water for injections in bulk is obtained from water that complies with the regulations on water intended for human
consumption laid down by the competent authority or from purified water. It is produced either: 16
– by distillation in an apparatus of which the parts in contact with the water are of neutral glass, quartz or a
suitable metal and which is fitted with an effective device to prevent the entrainment of droplets; The correct
maintenance of the apparatus is essential. the first portion of the distillate obtained when the apparatus begins
to function is discarded and the distillate is collected; or 17
– by reverse osmosis, which may be single-pass or double-pass, coupled with other suitable techniques such as
deionisation and/or ultrafiltration. 18
Correct operation monitoring and maintenance of the system are essential. 19
In order to ensure the appropriate quality of the water, validated procedures, in-process monitoring of the
electrical conductivity, and regular total organic carbon and microbial monitoring are applied. 20
Water for injections in bulk is stored and distributed in conditions designed to prevent growth of micro-organisms
and to avoid any other contamination. 21
Microbiological monitoring. During production and subsequent storage, appropriate measures are taken to
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ATCC 9027 57
30-35 °C
NCIMB 8626 58
18-24 h 63
62
30-35 °C
66
≤ 3 days 67
CIP 82.118 59
NBRC 13275 60
Bacillus subtilis 68
ATCC 6633 70
Casein soyabean digest agar or R2A agar 77
casein soyabean digest broth 74 ≤ 100 CFU 78
30-35 °C 75
30-35 °C 79
NCIMB 8054 71
18-24 h 76
such as:
69
≤ 3 days 80
CIP 52.62 72
NBRC 3134 73
Total organic carbon (2.2.44): maximum 0.5 mg/L. 81
Conductivity. Determine the conductivity off-line or in-line under the following conditions. 82
EQUIPMENT 83
Conductivity cell: 84
– electrodes of a suitable material such as stainless steel; 85
– cell constant: the cell constant is generally certified by the supplier and is subsequently verified at suitable
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35 118
1.5 119
40 120
1.7 121
45 122
1.8 123
50 124
1.9 125
55 126
2.1 127
60 128
2.2 129
65 130
2.4 131
70 132
2.5 133
75 134
2.7 135
80 136
2.7 137
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5.6 168
2.6 169
5.7 170
2.5 171
5.8 172
2.4 173
5.9 174
2.4 175
6.0 176
2.4 177
6.1 178
2.4 179
6.2 180
2.5 181
6.3 182
2.4 183
6.4 184
2.3 185
6.5 186
2.2 187
6.6 188
2.1 189
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Acidity or alkalinity. To 20 mL add 0.05 mL of phenol red solution R. If the solution is yellow, it becomes red on
the addition of 0.1 mL of 0.01 M sodium hydroxide; if red, it becomes yellow on the addition of 0.15 mL of
0.01 M hydrochloric acid. 214
Conductivity: maximum 25 µS·cm− 1 for containers with a nominal volume of 10 mL or less; maximum 5 µS·cm− 1
for containers with a nominal volume greater than 10 mL. 215
Use equipment and the calibration procedure as defined under Water for injections in bulk, maintaining the sample
temperature at 25 ± 1 °C. 216
Oxidisable substances. For containers with a nominal volume less than 50 mL: heat 100 mL to boiling with
10 mL of dilute sulfuric acid R, add 0.4 mL of 0.02 M potassium permanganate and boil for 5 min; the solution
remains faintly pink. 217
For containers with a nominal volume equal to or greater than 50 mL: heat 100 mL to boiling with 10 mL of dilute
sulfuric acid R, add 0.2 mL of 0.02 M potassium permanganate and boil for 5 min; the solution remains faintly
pink. 218
Chlorides (2.4.4): maximum 0.5 ppm for containers with a nominal volume of 100 mL or less. 219
15 mL complies with the limit test for chlorides. Prepare the standard using a mixture of 1.5 mL of chloride
standard solution (5 ppm Cl) R and 13.5 mL of water R. Examine the solutions down the vertical axes of the
tubes. 220
For containers with a nominal volume greater than 100 mL, use the following test: to 10 mL add 1 mL of dilute
nitric acid R and 0.2 mL of silver nitrate solution R2. The solution shows no change in appearance for at least
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