Pharmaceutical Water

PHAR 361
PHARMACEUTICAL TECHNOLOGY
Prof. Dr. Buket Aksu

E-mail: buket.aksu@altinbas.edu.tr
Altınbaş University Buket AKSU Buket AKSU@altinbas.edu.tr PHAR478 Quality assurance and regulations
Course Topics
➢ Pharmaceutical calculations I & II

➢ Unit operations
➢ Rheology
➢ Pharmaceutical water/ Solutions
➢ Solutions
➢ Semi solids (cream, ointments, gels)
➢ Disperse systems
➢ Suspensions
➢ Emulsions
➢ Emulsions (including HLB calculations)
➢ Suppository
Altınbaş Üniversitesi Prof. Dr. Buket Aksu buket.aksu@altinbas.edu.tr PHAR 361 – Pharmaceutical Technology
PHARMACEUTICAL
WATER
PHARMACEUTICAL WATER
Key Terminology
• Pharmaceutical water
• Water for injection
• Water types in different pharmacopeias
• Pyrogen
• Rabbit test / LAL test
• Distillation, Osmosis, Deionization
WATER (AQUA, EAU)
Most preferred solvent and carrier in pharmacy
▪ Suitable structure with the body liquids
▪ Its characteristic of being physically inert
Used in pharmaceutical applications

▪ As a raw material
▪ As excipient
▪ As solvent
▪ During synthesis, during production of the finished product
▪ As a cleaning agent for the equipment, primary packaging materials
WATER (AQUA, EAU)
➢Tap water from daily life contains:
▪ Ions (calcium, iron, magnesium, potassium and sodium)
▪ Organic substances from the trees
▪ Other gases in the atmosphere
WATER (AQUA, EAU)
To prepare water suitable for pharmaceutical applications
1. Removal of the undissolved substances from the water to be used
for drinking by using the methods such as sedimentation, filtration
and ion exchange,
2. Fixation of the taste with the processes of ventilation, chlorination

and coal-filtration and cleaning up from pathogenic microorganisms
WATER (AQUA, EAU)
*But, the water prepared using this method is not pure enough to be
used in pharmaceutical applications
Different methods for the preparation

of water to be used for pharmaceutical means are indicated
in pharmacopeias.
1. Drinking water
2. Pure water
Groups of Water According

Water Types Recorded in Pharmacopeias 3. Sterilized pure
to US Pharmacopeia
water
American Pharmacopeias (USP 27) 4. Water for injection
According to American pharmacopeia, there are 8 5. Sterile water for

groups of water injection
6. Sterile water for

inhalation
7. Sterile and
bacteriostatic water
for injection

irrigation
1. Drinking water
2. Pure water

Drinking Water 3. Sterilized pure
to US Pharmacopeia
water
• Derived from a public water utility, private water supply or

4. Water for injection
both
• Used in the first phase of cleaning pharmaceutical devices 5. Sterile water for
injection
• The minimum quality of water required for the preparaton
of bulk pharmaceutical ingredients 6. Sterile water for
inhalation
• Should not contain heavy metals, zinc salts, volatile
substances, Coliform microorganisms and other harmful 7. Sterile and
microorganisms bacteriostatic water
for injection
• Should not contain strong acid and alkaline (ph 6.2-8),
• Should be without color and odor and clear. irrigation
1. Drinking water
2. Pure water

Pure Water 3. Sterilized pure
to US Pharmacopeia
water
• Drinking water that is prepared and purified by 4. Water for injection

▪ Deionization
▪ Distillation 5. Sterile water for
injection
▪ Reverse osmosis
▪ Filtration inhalation
• Excipient in the production of non parenteral 7. Sterile and

preparations for injection

irrigation
1. Drinking water
2. Pure water

Sterilized Pure Water 3. Sterilized pure
to US Pharmacopeia
water
• Prepared by packing and sterilizing the purified 4. Water for injection

water
• Used for the preparation of dosage types, but not injection
parenteral ones 6. Sterile water for
inhalation
7. Sterile and
for injection

irrigation
1. Drinking water
2. Pure water

Water for Injection 3. Sterilized pure
to US Pharmacopeia
water
• Pure water prepared from the drinking water using 4. Water for
injection
the appropriate methods such as distillation or
reverse osmosis according to the features indicated 5. Sterile water for
injection
in monographs
• Used as excipient in the production of parenteral inhalation
preparations 7. Sterile and

• The bacterial endotoxine limit cannot exceed 0.25 for injection
EU/mL 8. Sterile water for
irrigation
1. Drinking water
2. Pure water

Sterile Water for Injection 3. Sterilized pure
to US Pharmacopeia
water
• Prepared by sterilizing the water for injection and 4. Water for injection
packed in single dosage containers which are not larger
than 1 L. 5. Sterile water for
injection
• Indicated by its label that it does not contain anti- 6. Sterile water for
microbial substance or any additives, inhalation
• Sterile diluent for parenteral products but if not 7. Sterile and

isotonic, not appropriate for intravenous application, for injection
• The bacterial endotoxine limit cannot exceed 0.25 8. Sterile water for
EU/mL irrigation
1. Drinking water
2. Pure water

Sterile Water for Inhalation 3. Sterilized pure
to US Pharmacopeia
water
• Sterilized and appropriately packed version of 4. Water for injection

water for injection, 5. Sterile water for
• Cannot be used for the preparation of injection
preparates for injection or other steriles 6. Sterile water for

inhalation
• Intended to be used in inhalators and in the
7. Sterile and
preparation of inhalation solutions bacteriostatic water
• The bacterial endotoxine limit cannot exceed 0.5

for injection
EU/mL. 8. Sterile water for

irrigation
1. Drinking water
2. Pure water

Sterile and Bacteriostatic Water for Injection 3. Sterilized pure
to US Pharmacopeia
water
• Water prepared by appropriate packing and sterilizing

water for injection that contains anti microbial substance.
• Used for the preparation of preparates with single dose or 5. Sterile water for
injection
multi-dose not more than 30 mL.
• The bacterial endotoxine limit cannot exceed 0.5 EU/mL. inhalation
• Indicated by its label : 7. Sterile and

▪ the materials it contains for injection
▪ the amount of those materials
▪ notification that it cannot be used on new born babies. 8. Sterile water for
irrigation
1. Drinking water
2. Pure water

Sterile Water for Irrigation 3. Sterilized pure
to US Pharmacopeia
water
• Similar to sterile water for injection 4. Water for injection

• Main difference: packaging volume higher than 1 L.
injection

inhalation
7. Sterile and
for injection

irrigation
1. Pure water
Water Types Recorded in Pharmacopeias
Water Types According to

European Pharmacopeia
European Pharmacopeia (Ph. Eur. 2002)
2. High-purity water
There are 4 groups of water according to
European pharmacopeia

injection
1. Pure water
Potable Water

• Properties not indicated by European
pharmacopoeia but it should comply with the 2. High-purity water
standards determined by the competent
authority,
• Source feed water for the production of 3. Water for injection
pharmacopoeial grade waters
• Used for chemical syntheses and the pre- 4. Sterile water for
cleaning of pharmaceutical production injection
equipment, unless otherwise stated.
1. Pure water
Pure Water

• Used for the preparation of medical preparates
that do not necessitate sterile and/or apyrogenic 2. High-purity water
water,
• If could pass the endotoxine test, then can also be
used for the preparation of dialysis solutions,
• Prepared in compliance with the usage standards 3. Water for injection
determined by competent authorities through
distillation, ion exchange or the appropriate
method. 4. Sterile water for
injection
• Separated into two
▪ packaged pure water
▪ unpackaged pure water
1. Pure water
Pure Water

Unpackaged pure water: Used for the
preparation of sterile medications and those
medication that do not have to be non-
pyrogenic. 3. Water for injection
Packaged pure water: products packaged and 4. Sterile water for

labeled in appropriate containers. injection
1. Pure water
High Purity Water

• Water used for the preparation of
pharmaceutical products for which the water 2. High-purity water
for injection is not used but high biological
quality water is required
• Prepared by ultrafiltration and de-ionization
and also by double reverse osmosis method by
using the water indicated by competent 4. Sterile water for
injection
authorities.
1. Pure water
High Purity Water

• Same standards with the water for injection;
but
• Less reliable preparation methods when compared
with distillation → can not be used as water for
injection
• An alternative of the water for injection in
▪ peritoneal dialysis solutions, 4. Sterile water for
injection
▪ eye preparates, and
▪ preparation of nose/ear preparates.
1. Pure water
Water for Injection

• Ensure consistent microbiological quality by
removing bacteria and bacterial endotoxins 2. High-purity water
• Should be acquired from the drinking water
with the proper characteristics
• The bacterial endotoxine limit cannot exceed 3. Water for injection
0.25 EU/mL.
• Same standards with purified water but 4. Sterile water for
additional requirements: conductivity, TOC injection
(total organic carbon test)
1. Pure water
Sterile Water for Injection

• Prepared by sterilization of the water for injection
• Bacterial endotoxin limit does not exceed 0.25 2. High-purity water
EU/mL,
• Used in cases where water has to be used as carrier or
solvent in parenteral preparations, 3. Water for injection
▪ Preparation of haemofiltration solutions,
▪ Hemodiafiltration solutions,
▪ Peritoneal dialysis solutions, 4. Sterile water for
▪ Ophthalmic preparations injection
▪ Otic/nasal preparations
▪ Cutaneous preparations
Water Types According to European

There are 3 groups of water 1. Water for Injections
according to European
Pharmacopeia
pharmacopeia
2. Purified Water
(Draft)
3. Water for preparation
of extracts
Water Types Used in Sterile Medical Products
Parenteral Water for Injection
Hemofiltration Solutions Water for Injection
Hemodiafiltration Solutions Water for Injection
Peritoneal Dialysis Solutions Water for Injection
Irrıgation Solutions Water for Injection
Ear /nasal preparations Purified
Cutaneous preparations Purified
Ophthalmic Purified
Water Types Used in Non-Sterilized Medical products
• Oral preparates............................. Purified
• Nebuliser solutions....................... Purified*
• Autic/nasal preparates..................Purified
• Rektal/vaginal preparates..............Purified
• Cutaneous Preparations…………..….Purified**
Water purification methods
2 types of pharmaceutical water
▪ Pure water
▪ Water for injection
➢Similar standards
➢Difference: bacterial count and bacterial endotoxine test
Pharmaceutical water is prepared by various water purification
methods using drinking water as the source feed
Distillation
• One of the earliest methods used for water
purification
▪ Evaporation of water
▪ Condensation of water to clear it from impurities:
Transaction of distillation
• Help to clean out the inorganic substances and
organic substances which do not have a vaporization
degree approximate to the water.
Deionization (demineralization)
• Deionized water : water cleaned from the unnecessary ions,
▪ The use of ion exchange resins that require periodic regeneration
• Compared to distillation more inexpensive and quick production
• Cation exchange resins: Contain acid group and hold the cations of
the liquid, regeneration with hydrochloric or sulfuric acid
• Anion exchange resins: Contain alkali groups and hold the anions,
regeneration with sodium or potassium hydroxide
Free endotoxin is negatively charged, which type of resin would you use?
Ion exchange resins
Constant networks not soluble in the solvents used in laboratories and
chemically inert
Ion
Exchangers
Inorganic Organic
Natural Synthetic Cation Anion
Deionization (demineralization)
Concerns for deionization units
• Anion and cation ion exchange resins cannot hold pyrogenic substance and
some organic compounds
• Deionization does not clarify the blurred water.
▪ Deionized water should not be used for the preparation of parenteral preparates
instead of distilled water,
▪ Use of fresh deionized water is preferred.
• During the acquisition, the first water should be discarded
Electrodeionization
• Mixed resin , selectively permeable membrane, and electric current
to provide a continous flow and continuous regeneration
• Deionization of water through the resin
• Separation into hydogen and hydroxide ions for regeneration
• Use of already partially purified water
• In pharmacy, water means distilled water
Reverse Osmosis
• Water purification technology that uses a semipermeable membrane
to remove ions, molecules, and larger particles from drinking water
• An applied external pressure is used to overcome osmotic pressure
• Kind of filtration process
Reverse Osmosis method
• Solute is retained on the pressurized side of

the membrane
• Solvent is allowed to pass to the other side.
➢ To be "selective", this membrane should
not allow large molecules or ions through
the pores, but should allow smaller
components of the solution (such as
solvent molecules) to pass freely.
Filtration
• Sand filters, carbon filters, cartridge filters
such as porous or media type
• Filtration from the suspended state to
remove particulates
• Microfiltration and ultrafiltration
• Reduction of dissolved materials
• Removal of particles, bacteria and pyrogens
Electrodialysis
▪ Separation of ions in an electrical
field
▪ Anion and cation permeable
membrane
▪ Separation of small molecule organic
materials and colloidal particles
Controls Conducted In The Water
Chemical Physical Biological
▪ TOC (total organic carbon)

test ▪ Assignment of dry residue ▪ Sterility test
▪ Conductivity test ▪ Clarity of water (Conducted microbiologically)
In Vivo Methods
Pyrogen Test
Pyrogen: "fire maker" in Greek
• describes the complex material that cause high fever and several
reactions when injected more than a certain amount
• bacteria, fungal and virus stemming,
• water soluble, that passes from normal filtration with a structure
resistant to normal sterilization heat.
• As it is very easy for microorganisms to reproduce in the water,
parenteral preparates must use the water which is cleaned from
bacterial endotoxines
• A pyrogenic test in the laboratory
• to understand whether the prepared water contains pyrogenic substance or not,
• The first method that was used for pyrogen assignment
• the USP rabbit test in 1940s, which is still registered at TF 1974, USP 27 and Ph. Eur.
2002,
• This test contains electrodes to measure the temperature, their indicators and a
recorder.
Rabbits subjected for the application in the pyrogen test

Requirements of the tests:
▪ Deviation in ambient temperature no more than 5oC
▪ No excitement or disturbance to the animals
▪ Temperature deviation in animals no more or less than 0.3oC
▪ Control 4 hours, 1 hour and 30 minutes before the test
▪ Hungry rabbits
▪ Non pyrogenic food before 12 hours
▪ Isotonic water
▪ 30 minutes after injection body temperature will be measured for 6 hours
• 3 rabbits will be tested
▪ Total temperature distance in 3 animals less than 1.4
▪ Total temperature distance in 1 animal less than 0.6
➢ no pyrogen in water
• If values are high : repetition with 5 animals
▪ Total temperature difference in 8 animals more than 3.7
▪ Total temperature difference in 3 out of 8 animals more 0.6
➢ Presence of pyrogen in water
➢Expensive and long process
→Lost its characteristic of being a quantitative method.
In Vitro Methods
LAL Test (Bacterial Endotoxin Test)
▪ Use of Lysate acquired from the Ameobocytes (blood cell) in
bloodstream of shallow sea creatures of crab-like Limulus polyphemus
with the bacterial endotoxine in vitro conditions since 1970s
Shallow sea animals like the crab named Limuluspolyphemus
• Reaction of LAL (Limulus Amöbosit Lizat) with bacterial endotoxine is
the basis
• Used for the detection and quantification of bacterial endotoxins
• Formation of a clot by inactivation of endotoxin
• More accurate and reliable than the rabbit test
• should be used unless otherwise stated in Ph. Eur. 200 and USP 27
• Issues to be considered
• No presence of antibiotics
• Existence of amino acids might provide misleading results
• Aseptic conditions should be used
• Appearance of a clot (gel)
• In 15 minutes: + result
• After 20 minutes of waiting time: + result
• If viscous: - result
Validation of water purification, storing and
distribution systems
• To provide the reliability of pharmaceutical water purification, storing
and distribution systems; the validation of system is necessary
• Information about the assurance and documentation of the

appropriate production of a product for which the quality
characteristics were previously determined
Typical Validation Plan for water systems
Determination of the standards that belong to transaction
parameters and the quality characteristics
Defining the system and sub systems to provide the production at the
necessary level from the existing water resources
Selection of equipment control and tracking technologies
Development of the IQ(Installation Qualification) step according to device

calibrations, and to the necessary tests for installing and control of
appropriate waster system with the design
Typical Validation Plan for water systems
Development of the OQ (Operational Qualification) step that consists of tests
and controls indicating that the system alarms and controls are working in
reliable and appropriate ways
Implementation of the existing or retrospective PQ (Performance Qualification)
indicating the repeatability of the system for an appropriate time
Provide the sustainability of validation program (continues validation life cycle)
Develeopment of a program to review periodically the performance and quality

of the system
Completing the protocol and documentation

Pharmaceutical Water

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PHAR 361

Prof. Dr. Buket Aksu

➢ Pharmaceutical calculations I & II

Used in pharmaceutical applications

2. Fixation of the taste with the processes of ventilation, chlorination

Different methods for the preparation

Groups of Water According

American Pharmacopeias (USP 27) 4. Water for injection

According to American pharmacopeia, there are 8 5. Sterile water for

6. Sterile water for

8. Sterile water for

Groups of Water According

• Derived from a public water utility, private water supply or

Groups of Water According

• Drinking water that is prepared and purified by 4. Water for injection

• Excipient in the production of non parenteral 7. Sterile and

8. Sterile water for

Groups of Water According

• Prepared by packing and sterilizing the purified 4. Water for injection

8. Sterile water for

Groups of Water According

preparations 7. Sterile and

Groups of Water According

• Sterile diluent for parenteral products but if not 7. Sterile and

Groups of Water According

• Sterilized and appropriately packed version of 4. Water for injection

preparates for injection or other steriles 6. Sterile water for

• The bacterial endotoxine limit cannot exceed 0.5

EU/mL. 8. Sterile water for

Groups of Water According

• Water prepared by appropriate packing and sterilizing

• Indicated by its label : 7. Sterile and

Groups of Water According

• Similar to sterile water for injection 4. Water for injection

6. Sterile water for

8. Sterile water for

Water Types According to

4. Sterile water for

Water Types According to

Water Types According to

Water Types According to

Packaged pure water: products packaged and 4. Sterile water for

Water Types According to

Water Types According to

Water Types According to

Water Types According to

Water Types According to European

Natural Synthetic Cation Anion

• Solute is retained on the pressurized side of

Chemical Physical Biological

▪ TOC (total organic carbon)

Rabbits subjected for the application in the pyrogen test

Shallow sea animals like the crab named Limuluspolyphemus

• Information about the assurance and documentation of the

Selection of equipment control and tracking technologies

Development of the IQ(Installation Qualification) step according to device

Provide the sustainability of validation program (continues validation life cycle)

Develeopment of a program to review periodically the performance and quality

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