7/21/2020 Pharmaceutical Water : Pharmaceutical Guidelines

Pharmaceutical Water
Types of Water, Non potable water, Portable water, Purified water, Water For Injection (WFI), Sterile water for injection, Bacteriostatic WFI, Sterile water for Inhalation,
Sterile water for irrigations, Water for hemodialysis, Pure steam, Specification of Water

A. Introduction
Water is one of the major commodities used by the pharmaceutical industry. It is widely used as a raw material, ingredient, and solvent in the
processing, formulation, and manufacture of pharmaceutical products, active pharmaceutical ingredients (APIs) and intermediates, and analytical
reagents. It may present as an excipient, or used for reconstitution of products, during synthesis, during production of finished product, or as a
cleaning agent for rinsing vessels, equipment and primary packing materials etc.

There are many different grades of water used for pharmaceutical purposes. Several are described in USP monographs that specify uses,
acceptable methods of preparation, and quality attributes. These waters can be divided into two general types: bulk waters, which are typically
produced on site where they are used; and packaged waters, which are produced, packaged, and sterilized to preserve microbial quality throughout
their packaged shelf life. There are several specialized types of packaged waters, differing in their designated applications, packaging limitations, and
other quality attributes. Different grades of water quality are required depending on the different pharmaceutical uses.

There are also other types of water for which there are no monographs. These are all bulk waters, with names given for descriptive purposes only.
Many of these waters are used in specific analytical methods. These non-monographed waters may not necessarily adhere strictly to the stated or
implied modes of preparation or attributes.

Related: Removal of Pathogens from Water Systems

B. Types of Water Used:

Water is the most common aqueous vehicle used in pharmaceuticals. There are several types of water are used in the preparation of drug product,
such as;

1. Non-potable water:
Non-potable water is water that is not of drinking water quality, but which may still be used for many other purposes, depending on its quality. Non-
potable water is generally all raw water that is untreated, such as that from lakes, rivers, ground water, springs and ground wells.
Purposes:
• cleaning of outer surface of the factory
• used in garden
• washing vehicles etc

2. Portable water:
Portable water is not suitable for general pharmaceutical use because of the considerable amount of dissolved solids present. These dissolved solids
consist chiefly of the chlorides, sulphates and bicarbonates of Na, K, Ca and Mg. A 100 ml portion of official water contains not more than 100 mg of
residue (0.1%) after evaporation to dryness on a steam bath.
Purposes:
• To use as drinking water
• Washing and the extraction of crude drugs
• Preparation of products for external use
Related: Difference Between Purified Water and De-mineralized Water

3. Purified water:
Purified water is used in the preparation of all medication containing water except ampoules, injections, some official external preparations such as
liniments. Purified Water must meet the requirements for ionic and organic chemical purity and must be protected from microbial contamination. The
minimal quality of source or feed water for the production of Purified Water is Drinking Water.

Related: Purified Water Storage and Distribution System

Purposes:
• For the Production of non-parenteral preparation/formulation
• For the Cleaning of certain equipment used in non-parenteral product preparation
• For Cleaning of non-parenteral product-contact components

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• For All types of tests & assay

• For the Preparation of some bulk chemicals
• For the preparation of media in microbiology laboratories
Preparation technique:
• Deionization
• Distillation
• Ion exchange
• Reverse osmosis
• Filtration etc.

Related: Purified Water System Validation

4. Water For Injection (WFI):

Water for Injection is a solvent used in the production of parenteral and other preparations where product endotoxin content must be controlled, and
in other pharmaceutical applications Water For Injection (WFI) is sterile, non pyrogenic, distilled water for the preparation of products for parenteral
use. It contains no added substance and meets all the requirements of the tests for purified water. It must meet the requirements of the pyrogen
test. The finished water must meet all of the chemical requirements for Purified Water as well as an additional bacterial endotoxin specification. Since
endotoxins are produced by the kinds of microorganisms that are prone to inhabit water, the equipment and procedures used by the system to purify,
store, and distribute Water for Injection must be designed to minimize or prevent microbial contamination as well as remove incoming endotoxins
from the starting water. Water for Injection systems must be validated to reliably and consistently produce and distribute this quality of water.
Purposes:
• For the production of parenteral products/formulation
• For cleaning of parenteral product-contact components
Preparation technique:
• Distillation
• Reverse osmosis
• Membrane process
Storage condition:
• It can be stored for periods up to a month in special tanks containing ultraviolet lamps. When this freshly prepared water is stored and sterilized in
hermitically sealed containers, it will remain in good condition indefinitely.
• If autoclave is not available, freshly distilled water may be sterilized by boiling the water for at least 60 minutes in a flask stoppered with a plug of
purified non absorbent cotton covered with gauze, tin-foil or stout non absorbent paper; or the neck of the flask may be covered with cellophane and
tightly fastened with cord.

Related: Water for Injection (WFI) System Validation Process

5. Sterile water for injection:

It’s specifications are provided in USP monograph for water for injection, sterilized and packaged in suitable single-dose containers, preferably of
type I glass, of not larger than 1000 ml size. It meets the requirements of the sterility test and pyrogen test and other tests under purified water.
Purposes:
• Used for extemporaneous preparation compounding
• Used as a sterile diluent for parenteral products
Preparation technique:
• By distillation of water for injection (WFI)

6. Bacteriostatic WFI:
This is sterile Water for Injection containing bacteriostatic (antimicrobial) agents. It may be packed in single-dose containers of not larger than 5 ml
size and in multiple-dose containers of not larger than 30 ml size, the label of which indicates the name and the proportion of added agent.
Purposes:
• Used as a diluents in the preparation of parenteral products
Preparation technique:
• By using sterile water for injection

7. Sterile water for Inhalation:

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Sterile water for Inhalation is Water for Injection that is packaged and rendered sterile and is intended for use in inhalators and in the preparation of
inhalation solutions. It carries a less stringent specification for bacterial endotoxins than Sterile Water for Injection, and therefore, is not suitable for
parenteral applications.
Purposes:
• Preparation of use in inhalators
• Preparation of inhalant solutions
Preparation technique:
• By sterilization of water for injection

8. Sterile water for irrigations:

Sterile water for irrigations is Water for Injection packaged and sterilized in single-dose containers of larger than 1 L in size that allows rapid delivery
of its contents. It need not meet the requirement under small-volume injections.
Purposes:
• To bath and moisten body tissue
• Performing urologic procedure for surgeon
Preparation technique:
• From water for injection
Example:
• Surgical irrigation solution (Splash solution)
• Urologic irrigation solution
• Glycine solution
• Sorbitol solution

9. Water for hemodialysis:

Water for hemodialysis is used for hemodialysis applications. It may be packaged and stored in unreactive containers that preclude bacterial entry.
The term “unreactive containers” implies that the container, especially its water contact surfaces, are not changed in any way by the water, such as
by leaching of container-related compounds into the water or by any chemical reaction or corrosion caused by the water. The water contains no
added antimicrobials and is not intended for injection.
Purposes:
• For the dilution of hemodialysis concentrate solution
Preparation technique:
• From safe drinking water

10. Pure steam:

Pure steam is also sometimes referred to as “clean steam”.
Purposes:
• To remove any co-deposited impurity residues
• For air humidification in controlled manufacturing environments
• Used in steam sterilization of equipment and porous loads
• For cleaning the places where condensate directly comes in contact with official articles, product contact containers, and surfaces.

Water miscible solvents:

Although water miscible solvents are used in parenterals, principally to enhance drug solubility, it is important to mention that they also serve as
stabilizers for those drugs that degrade by hydrolysis. A water miscible solvent must be selected with grade care for it must not be irritating, toxic, or
sensitizing, and it must not exert an adverse effect on the ingredients of the formulation. Solvents that are miscible with water are:
• dioxolanes
• dimethylacetamide
• butylene glycol
• polyethylene glycol 400 and 600
• propylene glycol
• glycerin and
• ethyl alcohol

Water immiscible solvents include:

• Fixed oil
• ethyl oleate

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• Isopropyl myristate, and

• Benzyl benzoate.

C. Specification of Water

I. Specification of Distilled Water/Water for Injection

S. No Parameters Specifications
1. Appearance clear, colorless, no visible particles
2. Odor Odorless
3. pH 5.0-7.0
4. Acidity or alkalinity NMT 0.1 ml of 0.01M NaOH/Hcl
5. Chloride 0 ppm
6. Oxidizable Substances 0 ppm
7. Sulphate 0 ppm
8. Total hardness 0 ppm
9. Total dissolved solid (TDS) NMT 10.0 ppm
10. Conductivity NMT 0.1ms
11. Microbial count 10 cfu/100 ml

II. Specification of Purified Water

S. No Parameters Specifications
1. Appearance clear, colorless, no visible particles
2. Odor Odorless
3. pH 5.0-7.0
4. Acidity or alkalinity NMT 0.1 ml of 0.01M NaOH/Hcl
5. Chloride 0 ppm
6. Oxidizable Substances 0 ppm
7. Sulphate 0 ppm
8. Total hardness 0 ppm
9. Ammonia 0.2 ppm
10. Heavy metal 0.1 ppm
11. Nitrate 2.0 ppm
12. Total dissolved solid (TDS) NMT 1.0 ppm
13. Conductivity NMT 1.0ms
14. Microbial count 100 cfu/ ml & absence of pathogenic bacteria

III. Specification of Portable water

S. No Parameters Specifications
1. Appearance clear, colorless, no visible particles
2. Odor Odorless
3. pH 6.5-8.5
4. Chloride NMT 250 ppm
5. Aluminum 0.2 mg/L
6. Arsenic 0.01 mg/L
7. Fluoride 1.5 mg/L
8. Boron 0.3 mg/L
9. Sulphate NMT 400 ppm
10. Sodium NMT 200 ppm
11. Copper NMT 1.0 ppm
12. Total hardness NMT 500 ppm
13. Total dissolved solid (TDS) NMT 1000 ppm
14. Iron content NMT 0.3 ppm

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15. Turbidity (as SiO2) NMT 5.0 ppm

16. Dissolved oxygen NMT 5.0 ppm

17. Manganese NMT 0.1 ppm
18. Arsenic NMT 0.05 ppm
19. Lead NMT 0.1 ppm
20. Total alkalinity NMT 500 ppm
21. Suspended solid (Rust, Mud, Particles etc) 0 ppm
22. Microbial count 500 cfu/ ml & absence of pathogenic bacteria

IV. Specification of sterile Water for Injection

S. No Parameters Specifications
1. Appearance clear, colorless, no visible particles
2. Odor Odorless
3. pH 5.0-7.0
4. Acidity or alkalinity NMT 0.1 ml of 0.01M NaOH/Hcl
5. Chloride 0 ppm
6. Oxidizable Substances 0 ppm
7. Sulphate 0 ppm
8. Total hardness 0 ppm
9. Ammonia 0.2 ppm
10. Heavy metal 0.1 ppm
11. Nitrate 2.0 ppm
12. Total dissolved solid (TDS):
· Upto 30 ml size 40.0 ppm
· 30 ml – 100 ml size 30.0 ppm
· From 100 ml to above 20.0 ppm
13. Conductivity NMT 1ms
14. Microbial count 100 cfu/ ml & absence of pathogenic bacteria
15. Pyrogen test Meets the USP standard
16. Sterility test Meets the USP standard

Comparison of a selection of parameters concentrations listed by WHO, the European Union and the EPA of Portable water.

Parameter World Health Organization European Union United States

Acrylamide “ 0.10 μg/ “
Arsenic 10μg/l 0.1 μg/l 10μg/l
Antimony ns 5.0 μg/l 6.0 μg/l
Barium 700μg/l ns 2 mg/L
Benzene 10μg/l 1.0 μg/l 5 μg/l
Benzo(a)pyrene “ 0.010 μg/l 0.2 μg/l
Boron 2.4mg/l 1,0 mg/l “
Bromate “ 10 μg/l 10 μg/l
Cadmium 3 μg/l 5 μg/l 5 μg/l
Chromium 50μg/l 50 μg/l 0.1 mg/L
Copper “ 2.0 mg/l TT
Cyanide “ 50 μg/l 0.2 mg/L
1,2-dichloroethane “ 3.0 μg/l 5 μg/l
Epichlorohydrin “ 0.10 μg/l “
Fluoride 1.5 mg/l 1.5 mg/l 4 mg/l
Lead “ 10 μg/l 15 μg/l
Mercury 6 μg/l 1 μg/l 2 μg/l

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Nickel “ 20 μg/l “
Nitrate 50 mg/l 50 mg/l 10 mg/L (as N)
Nitrite “ 0.50 mg/l 1 mg/L (as N)
Pesticides (individual) “ 0.10 μg/ l “
Pesticides — Total “ 0.50 μg/l “
Polycyclic aromatic hydrocarbons l “ 0.10 μg/ “
Selenium 40 μg/l 10 μg/l 50 μg/l
Tetrachloroethene and Trichloroethene 40μg/l 10 μg/l “

Also see: Types of Water Used in Pharmaceutical Processes

SUBMITTED BY:
MD. ABDUL BAKE*1, MR. ZUBAIR KHALID LABU2, KHURSHID JAHAN3
Address: *1 Product Development Officer, Gonoshasthaya Pharmaceuticals Limited, Dhaka, Bangladesh
2 Head of the Pharmacy Department, World University of Bangladesh, Bangladesh
3 Lecturer, Department of Pharmacy, World University of Bangladesh, Bangladesh

Email: Md. Abdul Bake* - abdul.bake@yahoo.com;

Zubair Khalid Labu - zubairlabu@yahoo.com;
Khurshid Jahan - nimmy45@yahoo.com

Ankur Choudhary is India's first professional pharmaceutical blogger, author and founder of Pharmaceutical Guidelines, a widely-read
pharmaceutical blog since 2008. Sign-up for the free email updates for your daily dose of pharmaceutical tips.
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