PHAR 307

Pharmaceutical
Water Systems

Dılek Ozyılmaz Pharm, MRSC

Gonul Basman MEng, MRSC
 Objective

▪ Types of Water for Pharmaceuticals

▪ Water System Requirements

▪ Methods of Purification

▪ Storage and Distribution

▪ Sampling and Testing

The importance of water in pharmacy

▪ Water is the one of the major raw materials

used by the pharmaceutical industry. It is
widely used as a raw material, ingredient,
and solvent in processing, formulation and
manufacture of pharmaceutical products,
active pharmaceutical ingredients (APIs) and
intermadiates, and analytical reagents.
▪ It may as an excipient or used for
reconstitution of products, during synthesis,
during production of finished product or as a
cleaning agent for rinsing vessels.
* 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 .
* These 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.
 Why is there different grades of water?
▪ High quality water is essential for manufacturing pharmaceuticals

▪ Quality of water should be specific for product quality

▪ Low quality of water can lead to..

✓product degradation
✓product contamination
✓Loss of product and profit
 Official Water Guidelines

▪ United States Pharmacopeia (USP)

▪ European Pharmacopeia (EP)

▪ International Pharmacopeia (IP)

▪ Japanese Pharmacopeia (JP)

 Types of Water (USP & EP)
▪ Non-potable
▪ Potable (drinking) Water
▪ Purified Water (PW)
▪ Highly Purified Water (EP only)
▪ Water for Injection (WFI)
▪ Sterile Purified Water
▪ Sterile Water for Injection
▪ Sterile Water for Irrigation
▪ Sterile Water for Inhalation
▪ Bacteriostatic Water for Injection
According to the European Pharmacopoeia (EP 5)
and the American Pharmacopeia (USP 27)
Types of Water (USP)
Use of water in Sterile Medicinal Products
 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 un
treated, such as that from lakes, rivers, ground water,
springs and ground wells.

Purposes:

* Cleaning for outer surface of the factory

* Used in garden
* Washing vehicles
 Potable (Drinking) Water
* Potable water is not suitable for general pharmaceutical
use because of the considerable amount of dissolved
solids present. These dissolve solids consist 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 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
 Purified Water (PW)

* Purified water is used in the preparation of all

medication containing water except ampoules,
injections and 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.
 Purified Water (PW)

Purposes:

* For the production of non-parenteral preparation

* For the cleaning of certain equipment used in non-
parenteral product preparation
* For cleaning of non-parenteral product-contact
components
* For all types of tests and assays
* For the preparation of some bulk chemicals
* For the preparation of media in microbial laboratories
 Purified Water Specifications
USP: “..prepared by distillation, reverse osmosis or any other
suitable method”
▪ Conductivity ≤ 1.3 µS/cm @ 25º C
▪ Total Organic Carbon (TOC) ≤ 500 ppb
▪ Microbial ≤ 100 cfu/ml
▪ No endotoxin requirement

EP: “..prepared by distillation, by ion exchange, reverse

osmosis or any other suitable method”
▪ Conductivity ≤ 4.3 µS/cm @ 20º C
▪ Total Organic Carbon (TOC) ≤ 0.5 mg/l
▪ Microbial ≤ 100 cfu/ml
▪ Endotoxin ≤ 0.25 EU/ml (only for dialysis)
 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 is
sterile, non pyrogenic, distilled water for the
preparation of produts 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 prufied water as well as an
additional bacterial endotoxin specification.
 Water For Injection (WFI)

* 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
* For cleaning of parenteral product
Storage Condition:
* It can be stored for periods up to a month in special tanks
containing ultraviolet lamps.
* 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 adsorbent cotton
covered with gauze.
 Water for Injection Distillation techniques
▪ There are 3 distillation still designs:

✓ Single-Effect (SE)
✓ Multi-Effect (ME)
✓ Vapour Compression (VC)
▪ Chemically and microbiologically purifies water
▪ Uses Plant Steam to convert feed water to pure steam
▪ Separator allows impurities to drop out of the pure steam
Water for Injection Distillation techniques
Multi-Effect Still (ME)
▪ Pure steam from first effect used to convert feed
water to pure steam in subsequent effects
Water for Injection Distillation Technique
Vapor Compression (VC)
▪ Uses plant steam to convert initial feed water to vapor (pure
steam)

▪ Pure steam is compressed, elevating temperature

▪ Compressed vapor is used to evaporate new feed water, giving

up latent heat and condensing as WFI
 Sterile Water For Injection

* Itsspecifications 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 diluents for parenteral products

* Sterile water for injection is generally prepared by

distillation of water for injection (WFI).
 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 larder 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.

* It is prepared by sterilization of water for injection.

 Sterile Water for Irrigations
* Sterilewater for irrigations is water for injection packaged
and sterilized in single dose containers of larger than 1L in
size that allow a rapid delivery of its contents. It need not
meet the requirement under small volume injections.

Purposes:
* The bath and moisten body tissue
* Performing urologic procedure for surgeon
 Water for Hemodialysis
* Water for hemodialysis is used for hemodialysis applications.
* It may be packaged and stored in un reactive containers
that preclude bacterial entry.

Purposes:

* For the dilution of hemodialysis concentrate solution

* It is prepared from safe drinking water

Water Quality Specifications
 Purification Stages
Pre-Treatment
• Particulate Trapping
• Chlorine Removal
• Microbial Reduction

Final Treatment
• Polishing
• Microbial Reduction

Storage & Distribution

• Suitably designed
• Prevent microbial and other contamination
 Purification Methods
Typical drug manufacturing facilities may use potable water in
both its raw form and with a variety of treatment steps until it
meets the quality requirements for Purified Water (PW) or Water
For Injection (WFI), including:

• filtration

• softening

• de-chlorination

• reverse osmosis

• de-ionization

• distillation
 Micro-Contamination
▪ Microorganisms – Biofilm formation

▪ Algae

▪ Protozoa
✓ Cryptosporidium
✓ Giardia
▪ Bacteria
✓ Pseudomonas
✓ Gram negative, non-fermenting bacteria
✓ Escherichia coli and coliforms
 Water Contact Materials

▪ Suitable materials include (Chemical and Heat

Compatible):

✓ Stainless steel Grade 316 or 316L

✓ Polypropylene (PP)
✓ Polyvinylidenedifluoride (PVDF)
✓ Perfluoroalkoxy (PFA)
 Quality Control Tests

▪ Physical controls
▪ Chemical controls
▪ Microbiological controls
▪ Pyrogen test
 Sampling

▪ There must be a sampling procedure

▪ Sample integrity must be assured
▪ Sampler training
▪ Sample point
▪ Sample size
 Physical Controls

*Colour
*Turbidity
*pH: Rinse the pH electrode several times with water
and at least twice with aqueous solution to be examined
(purified water sample) at 25 0C ± 0.10C. Note the pH
reading. The pH should be between 5 to 7.
*Conductivity (at 25°C)
Rinse the conductivity cell several times with carbon
dioxide free water and at least twice with aqueous
solution to be examined (purified water sample) at 25 0C
± 0.10C. The conductivity should not be more than 2.1
µS/cm
 Chemical Controls

* Total organic carbon

* Test for nitrates
* Test for heavy metals
* Test for copper
* Test for oxygen
 Microbial Controls
* Total Bacterial Count and Total Yeast:
* Test for Escherichia coli:
* Test for Salmonella Species:
* Test for Pseudomonas aeruginosa:Transfer 10 ml of the
sample into 100 ml of soyabean casein medium and incubate at
30ºC to 35ºC for 24-48 hours. After incubation, subculture a
loopful of the sample onto the surface of Cetrimide Agar and
incubate at 30 to 35° for 18 to 72 hours. If no growth of
microorganism is detected, the product passes the test.
* Test for Staphylococcus aureus:Transfer 10 ml of the
sample into 100 ml of Soyabean Casein Digest Medium
and incubate at 30ºC to 35ºC for 24-48 hours. After
incubation, subculture a loopful of the sample onto the
surface of Baird Parker Agar and incubate at 30 to 35°
for 18 to 72 hours. If no growth of microorganism is
detected, the product passes the test.
 PYROGENS
*A Pyrogen is defined as “a fever producing agent”
*Metabolic products of Microorganisms.
They are;

*Soluble
*Filterable
*Thermostable
*Non Volatile
 Sources of Pyrogen
*Solvents, excipients, additives, apparatus used
in manufacture, containers may be sources of
pyrogens.
*The method of storage in between preparation
and sterilization also may cause the
development of pyrogens.
*Hence every item must be apyrogenic and
method of storage must not allow any bacterial
growth.
 Test for pyrogens
*Pyrogen testing defines a process used by drug
manufacturers to determine if bacterial toxins are
present in vaccines and drugs that might cause fever
when used on humans.
 Rabbit Test
* The test consists of measuring the rise in body temperature in
healthy rabbits after the intravenous injection of a sterile test
solution or pharmaceutical water.

Requirements for the Rabbit Pyrogen Test:

* Rabbits must be healthy
* Must be individually housed between 20 and 23°C
* Not varies more than ± 3ºC.
* Equipment and material used in test (glassware and syringes
etc.) must be free from Pyrogens by heating at 250ºC for not less
then 30 minutes or any other method.
Procedure
Interpretation of pyrogen test

1.4
 Limitation of Rabbit test

* The rabbit test gives only a pass/fail result and is not

suitable for the control of endotoxin limit.
* It is not a quantitative test and less-well standardized.
* A gap between the observed pyrogenicity in rabbits and the
expected pyrogenicity in humans.
* It is not suitable for all product categories.
* It is expensive.
* It involves the use of animals.
* Radiopharmaceuticals cannot be detected in rabbit tests.
 LAL Test

* Limulus amebocyte lysate test.

* To measure the concentration of endotoxins of gram-
negative bacterial origin.
* Reagent: amoebocyte lysate from horseshoe crab, Limulus
polyphemus.
 Principle of LAL Test

* The addition of solution containing endotoxin to a

solution of lysate produce turbidity.
* The rate of reaction depends upon concentration of
endotoxin , the pH and the temperature.
* The endotoxin reference standard is the freeze dried.
* The test is also based on the primitive blood-clotting
mechanism of the horseshoe crab.
 Advantages of LAL Test

* Less variable
* In vitro test
* Easier to perform
* More sensitive
* Less Expensive
* Less Time consuming
* Can give Quantitative result
 Disadvantages of LAL Test

* Specific for gram (-)ve pyrogen only.

* Clotting enzyme is heat labile, pH sensitive.
* Possible interference problem.
Thank you for listening!

Questions?