Supplementary Training Modules on
Water
Good for Pharmaceutical
Manufacturing Practice Use
Water for Pharmaceutical Use
Part 2:
Water purification engineering
Presented by Dr. Errol Allcoc
30 June 2005, Pretoria, South Africa
[email protected] 083-459 6267
Module 2, Part 2: Water purification engineering Slide 1 of 25 WHO - EDM
Water for Pharmaceutical Use
Objectives
To examine the basic technology and requirements for:
1. Water treatment systems
2. Storage requirements
3. Sampling and testing
4. Different types of water used in pharmaceuticals
5. Microbial limits, disinfection
Module 2, Part 2: Water purification engineering Slide 2 of 25 WHO - EDM
Water for Pharmaceutical Use
Water system design
1. Pipes sloped so water does not pool and can
drain easily
2. Sanitary fittings & connections
3. Constructed of suitable materials such as
stainless steel
4. Circulate the water
5. Incorporate non-return valves (NRV)
Module 2, Part 2: Water purification engineering Slide 3 of 25 WHO - EDM
Water for Pharmaceutical Use
Further water treatment purification stages
downstream of the pre-treatment system
1. Filtration
2. Disinfection
3. Reverse osmosis or de-ionization
4. Distillation or ultra-filtration
Module 2, Part 2: Water purification engineering Slide 4 of 25 WHO - EDM
Water for Pharmaceutical Use
Water system design (1)
There should be no dead legs
Flow direction arrows
on pipes are important
Deadleg section
X <2D
If D=25mm & distance X is
greater than 50mm, we have
a dead leg that is too long.
Sanitary Valve
Water scours deadleg
Module 2, Part 2: Water purification engineering Slide 5 of 25 WHO - EDM
Water for Pharmaceutical Use
Water system design (2)
1. Ball valves are unacceptable
2. Bacteria can grow when
the valve is closed
3. The water is contaminated
as it passes through the valve Stagnant water
inside valve
Module 2, Part 2: Water purification engineering Slide 6 of 25 WHO - EDM
Water for Pharmaceutical Use
Water system design (3)
1. Sanitary pumps
2. Clamps and O rings
versus threaded fittings
3. Heat exchangers
4. Side arm level measuring devices are
unacceptable
Module 2, Part 2: Water purification engineering Slide 7 of 25 WHO - EDM
Water for Pharmaceutical Use
Typical de-ionizer schematic
from water softener
HCl NaOH
6 6
5 5
4 4
3 3
2 2
1 1
Water
must be Cationic column Anionic column Cartridge Cartridge
filter 5 µm filter 1 µm
kept UV light
circulating Eluates to
neutralization
Ozone generator
plant
Hygienic pump
Return to de-ioniser
Outlets or storage.
Drain line
Air break to sewer
Module 2, Part 2: Water purification engineering Slide 8 of 25 WHO - EDM
Up and Down Flow
Water for Pharmaceutical Use
DOWNFLOW :
No channeling
and better ion
capture,
but higher
risk of
UPFLOW :
clogging
Channeling
Used in
but lower
Polishing
risk of
clogging
Used in
Pretreatment
Module 2, Part 2: Water purification engineering Slide 9 of 25 WHO - EDM
SEM of Ion-Exchange Resin Bead
Water for Pharmaceutical Use
Bead diameter:
300 to 1200 µm
(0.3 to 1.2 mm)
Beads pores:
1 to 100 nm
(0.001 to 0.1 µm)
Bead dry weight
40 to 60%
Module 2, Part 2: Water purification engineering Slide 10 of 25 WHO - EDM
Ion-Exchange Resin Bead model
Water for Pharmaceutical Use
Fixed Anion
Counter Cation
Styrene
Cross linking Agent
(DVB)
Hydrating Water
Module 2, Part 2: Water purification engineering Slide 11 of 25 WHO - EDM
Reverse Osmosis
Water for Pharmaceutical Use
Reverse
Osmosis Osmosis
Osmotic P
pressure
1 2 1 2
Reverse osmosis
1 Feed water membrane (RO)
2 Purified water
Module 2, Part 2: Water purification engineering Slide 12 of 25 WHO - EDM
Water for Pharmaceutical Use
Reverse osmosis (RO) theory
High pressure Low pressure
Semi-permeable
membrane
Feed
water
under Purified water
pressure raw water
Permeate
Reject
water
water
drain or recycle
Module 2, Part 2: Water purification engineering Slide 13 of 25 WHO - EDM
Reverse Osmosis
Water for Pharmaceutical Use
Membrane
Feed Water Permeate
Reject
Module 2, Part 2: Water purification engineering Slide 14 of 25 WHO - EDM
Water for Pharmaceutical Use
Typical 2-stage RO schematic
Water from softener or de-ioniser
Second stage reject water goes back to first stage buffer tank
1st stage buffer tank
Branch First stage RO cartridge
1st stage reject concentrate
Branch
First stage filtrate feeds second stage RO
with
. excess back to 1st stage buffer tank
Air break
to sewer 2nd stage buffer tank
Second stage RO cartridge
High pressure
pump
Cartridge
filter 1 µm Hygienic pump
Second stage RO water
meets Pharmacopoeia Water returns to 1st stage buffer tank
standards Outlets or storage
Module 2, Part 2: Water purification engineering Slide 15 of 25 WHO - EDM
Water for Pharmaceutical Use
Use of reverse osmosis
Advantages
Disadvantages
Many uses
purified water
feeding of distillation units or ultra-filtration units
Water for Final Rinse
Water for Injections (if permissible)
Module 2, Part 2: Water purification engineering Slide 16 of 25 WHO - EDM
Water for Pharmaceutical Use
Ultra-filtration
Can be used for WFI or for Water For Final
Rinsing for parenteral manufacturing (if
permitted)
Removes organic contaminants, such as
endotoxins
Operation at 80°C, and sterilization at 121 °C
Module 2, Part 2: Water purification engineering Slide 17 of 25 WHO - EDM
Ultrafiltration
Water for Pharmaceutical Use
Ultrafilters are asymetric
membranes, sometimes P
composite
Under pressure,small size
molecules go through the
membrane,whereas molecules 1
larger then the NMWL are
retained
100
Module 2, Part 2: Water purification engineering Slide 18 of 25 WHO - EDM
Water for Pharmaceutical Use
1. Single-effect distillation
simple distillation, single effect
vapour compression, thermo compression
2. Multi effect distillation
multiple effect stills
3. Clean steam generators
used where steam can come into contact with product contact
surfaces, e.g. sterilization-in-place (SIP)
Module 2, Part 2: Water purification engineering Slide 19 of 25 WHO - EDM
Water for Pharmaceutical Use
Typical water storage and distribution schematic
Hydrophobic air filter
Feed Water & burst disc
from
DI or RO Cartridge
filter 1 µm Spray ball
Water must Optional
in-line filter
be kept 0,2 µm
circulating
UV light
Outlets
Heat Exchanger
Ozone Generator Hygienic pump Air break
to drain
Module 2, Part 2: Water purification engineering Slide 20 of 25 WHO - EDM
Water for Pharmaceutical Use
Disinfection (1)
Heat
One of the most reliable methods of disinfection
of water systems
Ozone
Produced easily
Leaves no residue
Module 2, Part 2: Water purification engineering Slide 21 of 25 WHO - EDM
Water for Pharmaceutical Use
Disinfection (2)
UV
1. UV does not “sterilize”
2. Flow rate critical
3. Post-irradiation recontamination may be an issue
4. Lamps have finite life
Other chemicals
1. XO2
2. Halogen
3. Formaldehyde
Module 2, Part 2: Water purification engineering Slide 22 of 25 WHO - EDM
UV Technology :
Electromagnetic Spectrum
Water for Pharmaceutical Use
Gamma rays X Rays U.V. Visible Infrared
10-10 10-7 10-6 10-4 10-3
Wavelength(m)
Ultraviolet radiation
Ultra short Short Medium Long wave
UV-C UV-B UV-A
100 200 280 315 400
Wavelength (nm)
Module 2, Part 2: Water purification engineering Slide 23 of 25 WHO - EDM
U. V. Technology
Water for Pharmaceutical Use
Relative
intensity
Wavelength
(nm)
185 254 313
Emission of a low pressure mercury lamp.
Module 2, Part 2: Water purification engineering Slide 24 of 25 WHO - EDM
Germicidal Action
Water for Pharmaceutical Use
100%
80%
60% 254nm
40%
20%
0%
240 260 280 300 320
Module 2, Part 2: Water purification engineering Slide 25 of 25 WHO - EDM
UV Technology
(185 + 254 nm)
Water for Pharmaceutical Use
Conversion of traces of Polishing technique only:
organic contaminants to may be overwhelmed if
charged species and organics concentration in
ultimately CO2 (185 + 254) feed water is too high.
Organics are converted,
Limited destruction of micro- not removed.
organisms and viruses (254) Limited effect on other
Limited energy use contaminants
Easy to operate
Good design required for
optimum performance.
Module 2, Part 2: Water purification engineering Slide 26 of 25 WHO - EDM
Contaminants Removal
Water for Pharmaceutical Use
CONTAMINANT STILL DI RO UF MF AC
IONS
ORGANICS
PARTICLES
COLLOIDS
BACTERIA
VIRUSES
GASES
UV : converts organic molecules to CO2 or charged molecules
Module 2, Part 2: Water purification engineering Slide 27 of 25 WHO - EDM
Water for Pharmaceutical Use
Sampling (1)
1. There must be a sampling procedure
2. Sample integrity must be assured
3. Sampler training
4. Sample point
5. Sample size
Module 2, Part 2: Water purification engineering Slide 28 of 25 WHO - EDM
Water for Pharmaceutical Use
Sampling (2)
1. Sample container
2. Sample label
3. Sample storage and transport
4. Arrival at the laboratory
5. Start of test
Module 2, Part 2: Water purification engineering Slide 29 of 25 WHO - EDM
Water for Pharmaceutical Use
Testing - setting specifications for purified water
or WFI - (1)
Ph. Eur. JP USP Int. Ph.
pH 5.0-7.0 5.0-7.0 5.0-7.0 pass test
Cl < 0.5 pass test - pass test
SO4 pass test pass test - pass test
NH4 < 0.2 < 0.05 - pass test
Ca/Mg pass test - - pass test
Nitrates < 0,2 pass test - pass test
Nitrites - pass test - -
Module 2, Part 2: Water purification engineering Slide 30 of 25 WHO - EDM
Water for Pharmaceutical Use
Testing - setting specifications for purified water
or WFI (2)
Ph. Eur. JP USP Int. Ph
Conductivity (µS/cm) - - < 1.3 -
Oxidizable subs. pass test pass test - pass test
Solids (ppm) < 10 < 10 - nmt(*) 10
TOC (ppm) - < 0.5 < 0.5 -
Heavy metals - - - pass test
CO2 - - - pass test
Module 2, Part 2: Water purification engineering Slide 31 of 25 WHO - EDM
Water for Pharmaceutical Use
Testing
1. Method verification
2. Chemical testing
3. Microbiological testing
test method
types of media used
incubation time and temperature
objectionable and indicator organisms
manufacturer must set specifications
Module 2, Part 2: Water purification engineering Slide 32 of 25 WHO - EDM
Water for Pharmaceutical Use
Water for Injections
1. International pharmacopoeia requirements for
WFI are those for purified water plus it must be
free from pyrogens
2. Usually prepared by distillation
3. Storage time should be less than 24 hours
4. Microbial limits must be specified
Module 2, Part 2: Water purification engineering Slide 33 of 25 WHO - EDM
Water for Pharmaceutical Use
Water for Final Rinse
Water for final rinse must be of the
same quality as the water required
for pharmaceutical preparation
Module 2, Part 2: Water purification engineering Slide 34 of 25 WHO - EDM
Water for Pharmaceutical Use
Pyrogens and endotoxins
1. Any compound injected into mammals which gives
rise to fever is a “Pyrogen”
2. Endotoxins are pyrogenic, come from Gram negative
bacterial cell wall fragments
3. Detect endotoxins using a test for lipopolysaccharides
(LPS)
rabbit test detects pyrogens
LAL test detects endotoxins
4. Ultrafiltration, distillation, & RO may remove
pyrogens
Module 2, Part 2: Water purification engineering Slide 35 of 25 WHO - EDM
Water for Pharmaceutical Use
Suggested bacterial limits (CFU /mL)
Sampling location Target Alert Action
Raw water 200 300 500
Post multimedia filter 100 300 500
Post softener 100 300 500
Post activated carbon filter 50 300 500
Feed to RO 20 200 500
RO permeate 10 50 100
Points of Use 1 10 100
Module 2, Part 2: Water purification engineering Slide 36 of 25 WHO - EDM
