Pharmaceutical Water Systems

Zahid Ali Baig Sante (Pvt) Limited

 WATER is most widely used and sometime most
expensive substance as raw material or ingredient
in Pharmaceuticals;

 Production
 Processing
 Formulation
 Cleaning

–Pharmaceutical waters used in the manufacture of

drugs or drug products are subject to the regulations of
the cGMPs whether or not the water remains in the final
product
 TYPES OF WATER

USP differentiate between various types of water:

• Drinking Water : Non Compendial but must comply

with requirements of EPA. Used as feed water for the
production of Pharmaceutical water
• Purified Water (PW) : Must meet the ionic and
organic purity and protected from microbial
proliferation. Used in production of oral products,
pharmaceutical application and bulk pharmaceuticals
• Water for Injection (WFI): Must meet the chemical
requirements of PW and in addition Bacterial
Endotoxin and microbial contaminations.
 USP Specifications in Practice

Purified water used for non-injectable drugs can accept a

small amount of microbial contamination and has no
specifications on endotoxin.

WFI used for injectable drugs are expected to be free from

micro organisms but since some micro organisms may be
encountered during sampling, an action limit of 10 CFU/100
ml is commonly specified.

In WFI endotoxin are a concern and if bacteria are

introduced to the system and killed, these bacteria will
release endotoxin. Therefore, strict measurement has to be
taken not to introduce any bacteria into the system and to
secure that the small amount of bacteria in the system has
no possibility to grow.
Basis of Water Selection on the Needs of

• the process

• the product

• the specific application

 Source of Raw Water

• Surface or ground water

• Well or borehole
• Municipal or civil – “tap water”
• Tanker Water ?
 Contaminants of water

• There is no pure water in nature, as it can contain up to

90 possible unacceptable contaminants:

• Contaminant groups:
– Inorganic compounds
– Organic compounds
– Solids
– Gases
– Micro-organisms
 Why purify raw water?

 To remove impurities to prevent product contamination.

 To control microbes to avoid contaminating products

 To avoid seasonal variations in raw water

 To remove regional impurities from poor quality water

 Pre Treatment Steps

 Primary filtration and multi-media filter

 Coagulation or flocculation

 Desalination

 Softening

 Chlorination
Pretreatment –
schematic
drawing float
operated excess water recycled
from deioniser
activated
carbon
To water
valve
air filter sand filter
filter softener &
DI plant
spray ball

Water is kept raw water in break tank

circulating

cartridge
filter
centrifugal pump 5 micrometers
air break to drain

« S” trap to sewer

Major components for Pharmaceutical Waters
DRINKING WATER
EPA Quality

Typical Treatment Steps

* Softening * Reverse Osmosis
* Dechlorination * Ultrafiltration
* Deionization * Distillation

PURIFIED WATER USP

DISTILLATION OR
REVERSE OSMOSIS

WATER FOR INJECTION

 Pharmaceutical Waters

 Purified Water
• Obtained by distillation, ion-exchange treatment,
• reverse osmosis, or other suitable process;
• Prepared from water complying with the regulations of
the federal Environmental Protection Agency (EPA) with
respect to drinking water;
• Contains no added substances

 Water for Injection

• Water for Injection (WFI) is water purified by distillation
or by reverse osmosis that contains no added
substances.
 USP Specifications: PW vs. WFI
PW (Purified WFI (Water for
Water) Injection)
Water conductivity < 1,3 μS/cm at < 1,3 μS/cm at 25°C*
and pH 25°C* pH 5-7 pH 5-7
Total Organic < 0.5 ppm < 0.5 ppm
Carbon (TOC)
Aerobic Microbial < 100 CFU/ ml < 10 CFU/100 ml
Contamination (<0.1 CFU/ml)
Endotoxin content Not Specified < 0.25 EU/ml
Production Obtained by Obtained by suitable
Methods suitable process process and purified
by distillation.
 REVERSE OSMOSIS

High pressure Low pressure Reverse osmosis may be

used to:
Semi-permeable  purified water
membrane

Feed  feeding of distillation units

water
or ultra-filtration units
under
raw water
Purified water  water for final rinse
pressure Permeate
Reject
water

water

drain or recycle
REVERSE OSMOSIS
RO System
 Water purification & distribution loop
Purification process
Distillation system

Reverse Electro-
Feed osmosis deionisation Tank
water

Tank

Distribution loop
• Water for Injection (WFI) Distillation
Technique

– Vapor Compression (VC)

• Uses plant steam to convert initial feedwater to
vapor (pure steam)
• Pure steam is compressed, elevating
temperature
• Compressed vapor is used to evaporate new
feedwater, giving up latent heat and
condensing as WFI
• Higher electrical demand, but lower steam
demand
Water for Injection (WFI) Distillation Technique

Multi-Effect Still (MES)

• Uses Plant Steam to convert feedwater to pure steam

• Separators allow impurities to drop out of the pure steam
• Pure steam from first effect used to convert feedwater to
pure steam in subsequent effects
 Bacteria in Pharmaceutical water systems
• The most common bacteria in water system is
Pseudomonas sps. which can tolerate a maximum
temperature of 45°C

• In rare cases Pathogens could be found. These can

tolerate a maximum temperature of 55°C

• Mesophile bacteria have ionophores helping them collect

and store minerals and thus have the potential to live
and grow in pharmaceutical water systems
 Bacteria in Pharmaceutical water
systems
Development of biofilm in water pipes and tanks is another
common source of endotoxin. Biofilm is an accumulation of
microbes (dead and live) on pipes and surfaces, particularly
near joints, elbows or dead legs. This film is removed by
high shearing forces or with chemical substances.

In order to grow in nature or in the laboratory, a bacterium

must have an energy source, a source of carbon and other
required nutrients, and a permissive range of physical
conditions such as O2 concentration, temperature, and pH.
 Sanitization
Heat
• One of the most reliable methods of disinfection of water
systems. Typically with hot water at 75-85ºC. Temperatures
above 85ºC will increase the risk for rouging or cavitations
Ozone
• Produced easily
• Leaves no residue
UV
• UV does not “sterilize”
• Flow rate critical
• Post-irradiation recontamination may be an issue
• Lamps have short life
Other chemicals
• Sodium Hypo-chlorite solution
 Sanitization

Bacteria and Endotoxin growth in ambient water system

Contamination CFU/ml
Aerobic Microbial

Endotoxin EU/ml
Acceptance limit CFU/ml
Acceptance limit EU/ml

Time
 Sanitization
Bacteria and Endotoxin growth in ambient water system
Contamination CFU/ml
Aerobic Microbial

Endotoxin EU/ml
Acceptance limit CFU/ml
Acceptance limit EU/ml

Sanitization Sanitization
Time
 Storage and Distribution

These can be divided in 3 different temperature

types:

• Hot water systems (self sanitised)

• Ambient water systems (needs sanitization)

• Cold water systems (needs sanitization)

 Hot Storage, Hot Distribution
Control Valve
(optional)

Steam
Hot
Storage
Tank

Cond.

Most Advantageous When: Least Advantageous When:

•Hot water is required •Ambient temperature water
•Hot water is generated required
•Microbial control is critical
 Ambient Storage, Ambient Distribution

(optional)
Control Valve

Coolant Ambient Steam

Storage Sanitizing /Cooling
Tank Heat Exchanger Coolant
Coolant
Coolant
T

Cond.

NOTE: Identical configuration for Cold Storage, Cold Distribution System

Most Advantageous When: Least Advantageous When:
•High peak demands for ambient or cold water •Sanitization will not fit into
•Water is generated at ambient temperature operating schedule
•There is adequate time for sanitization
 Storage and Distribution

Contact materials include:

– Pipes
– Valves and fittings
– Seals
– Diaphragms and instruments
– Tanks
– Pumps, etc.

• Proper selection of construction material to ensure

these are suitable for storage and distribution of
treated water
 Storage and Distribution

contact materials

• Factors to consider (including components)

– Compatibility and leaching effect
– Corrosion resistance
– Smooth internal finishing, ease of jointing
– Hygienic / sanitary design
 Water system contact materials

• Compatibility
– With temperature and chemicals used in the
system
• Leaching effect
– Non-leaching at temperature range
• Corrosion resistance
– Stainless steel Grade 316L to be used
– System passivated after installation and
modification according to SOP
 Water system contact materials

Suitable materials include:

– Stainless steel Grade 316 & 316L
– Polypropylene (PP)
– Polyvinylidenedifluoride (PVDF)
– Perfluoroalkoxy (PFA)
– Teflon, Silicone, Viton (gaskets, diaphragms)

• Unplasticized polyvinylchloride (uPVC) used for non-

hygienic designed water treatment equipment such
as ion exchangers and softeners
 Water system contact materials

• Smooth internal finish

– Biofilms and microbial contamination

– Crevices and roughness result in problem areas
associated with contamination and corrosion
– Mechanical and electro-polishing needed when
stainless steel is used
 Validation Strategy

a. Design/installation review

b. SOP development and confirmation

c. Demonstration and effectiveness

d. Data compilation and sign off

 V-Model ”Direct Impact” Systems

Commissioning Qualification Validation

PQ Test Plan
URS PQ • Process Validation
• Cleaning Validation
OQ Test Plan • Revalidation
FS (incl. FAT) OQ

IQ Test Plan
DS (incl. PDI)
IQ
FAT SAT
Impact assessment
Implementation

ISPE Baseline Guides– Volume 5: Commissioning and Qualification – March 2001

PDI: Pre Delivery Inspection

 IQ /OQ

IQ should involve the identification of all system elements, service

conduits/pipes and gauges and the preparation of a documented
record that all installed equipments satisfies the planned
requirements.

Identification and documenting of preventative maintenance and

general maintenance requirements

OQ is the studies of the critical variables of the operation of the

equipment or systems and will define the critical characteristics for
operation of the system or sub-system

It is important to assure that all operational test data conform with

pre-determined acceptance criteria

After OQ it should be possible to finalise the operating procedures

and operator instructions documentation
 Validation, Documentation and SOPs

• Validation means documented evidence that the

system function as designed, in a consistent and
effective manner, and in accordance to predetermined
criteria.

• Validation demonstrates that there is a high probability

of an acceptable outcome if the system is operated in
the same way as when it was validated

• To demonstrate consistency and continuing proper

operation, continuingly effective cleaning practices
and routine monitoring should be applied, SOPs
 SUMMARY

• The water distribution system is a rather unique system

in the pharmaceutical industry

• It is a continuous system (no batch manufacturing)

• The product (water) is extremely clean and free from

nutrient and minerals

• It is a closed system
 SUMMARY

The main concerns for water systems are:

• Try to keep it as a continuous and closed loop

• Don’t disturb it

• There should be no risk of stains or residue in the system

• Bacteria will however generate biofilm and this is the main

concern
 SUMMARY

• Material in components must be of high quality in order to

secure for no contamination

• Components should be leakage safe

• Components should secure high shear rates on all product

contacted surfaces

• Components should have no crevices

• Components should have no un-flushable pockets/ dead legs