Supplementary Training Modules on Water for Pharmaceutical Use Good Manufacturing Practice

Water for Pharmaceutical Use

Part 2: Water purification engineering
Presented by Dr. Errol Allcoc 30 June 2005, Pretoria, South Africa Errol.Allcock@microsep.co.za 083-459 6267

Module 2, Part 2: Water purification engineering

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Water for Pharmaceutical Use

Objectives
To examine the basic technology and requirements for:
1. 2. 3. 4. 5.

Water treatment systems Storage requirements Sampling and testing Different types of water used in pharmaceuticals Microbial limits, disinfection

Module 2, Part 2: Water purification engineering

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Water for Pharmaceutical Use

Water system design
1.

Pipes sloped so water does not pool and can drain easily
Sanitary fittings & connections Constructed of suitable materials such as stainless steel Circulate the water Incorporate non-return valves (NRV)
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2. 3.

4. 5.

Module 2, Part 2: Water purification engineering

Water for Pharmaceutical Use

Further water treatment purification stages downstream of the pre-treatment system
1. 2. 3. 4.

Filtration Disinfection Reverse osmosis or de-ionization Distillation or ultra-filtration

Module 2, Part 2: Water purification engineering

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Water for Pharmaceutical Use

Water system design (1)
There should be no dead legs
D
Flow direction arrows on pipes are important Deadleg section

If D=25mm & distance X is greater than 50mm, we have a dead leg that is too long.

<2D

Sanitary Valve Water scours deadleg

Module 2, Part 2: Water purification engineering

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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

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Water for Pharmaceutical Use

Water system design (3)
1. 2.

Sanitary pumps Clamps and O rings versus threaded fittings Heat exchangers Side arm level measuring devices are unacceptable

3. 4.

Module 2, Part 2: Water purification engineering

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Water for Pharmaceutical Use

Typical de-ionizer schematic
from water softener HCl NaOH

6
5 4 3 2 1

6 5 4 3 2 1

Water must be UV light kept circulating

Cationic column

Anionic column

Cartridge filter 5 m

Cartridge filter 1 m Ozone generator

Eluates to neutralization plant Hygienic pump Return to de-ioniser

Outlets or storage.
Drain line Air break to sewer

Module 2, Part 2: Water purification engineering

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Up and Down Flow Water for Pharmaceutical Use

DOWNFLOW : No channeling and better ion capture, but higher risk of clogging Used in Polishing

UPFLOW : Channeling but lower risk of clogging Used in Pretreatment

Module 2, Part 2: Water purification engineering

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SEM of Ion-Exchange Resin Bead Water for Pharmaceutical Use

Bead diameter: 300 to 1200 m (0.3 to 1.2 mm) Beads pores: 1 to 100 nm (0.001 to 0.1 m) Bead dry weight 40 to 60%
Module 2, Part 2: Water purification engineering Slide 10 of 25
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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

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Reverse Osmosis

Water for Pharmaceutical Use

Osmosis
Osmotic pressure
P

Reverse Osmosis

Feed water Purified water

Reverse osmosis membrane (RO)

Module 2, Part 2: Water purification engineering

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Water for Pharmaceutical Use

Reverse osmosis (RO) theory
High pressure Low pressure

Semi-permeable membrane

Feed water under pressure

raw water

Purified water

drain or recycle

Module 2, Part 2: Water purification engineering

Reject water

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Permeate water

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Water for Pharmaceutical Use

Membrane

Reverse Osmosis

Feed Water

Permeate

Reject

Module 2, Part 2: Water purification engineering

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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
Branch

First stage RO cartridge

Branch

1st stage buffer tank

1st stage reject concentrate

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 Second stage RO water meets Pharmacopoeia standards

Cartridge filter 1 m

Hygienic pump

Water returns to 1st stage buffer tank Outlets or storage

Module 2, Part 2: Water purification engineering

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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

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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 80C, and sterilization at 121 C

Module 2, Part 2: Water purification engineering

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Ultrafiltration

Water for Pharmaceutical Use

Ultrafilters are asymetric membranes, sometimes composite Under pressure,small size molecules go through the membrane,whereas molecules larger then the NMWL are retained

100

Module 2, Part 2: Water purification engineering

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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

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Water for Pharmaceutical Use

Typical water storage and distribution schematic
Feed Water from DI or RO Hydrophobic air filter & burst disc Cartridge filter 1 m

Spray ball

Water must be kept circulating

Outlets

Optional in-line filter 0,2 m UV light

Heat Exchanger
Ozone Generator Hygienic pump Air break to drain

Module 2, Part 2: Water purification engineering

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Water for Pharmaceutical Use

Disinfection (1)
Heat

One of the most reliable methods of disinfection of water systems Produced easily Leaves no residue

Ozone

Module 2, Part 2: Water purification engineering

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Water for Pharmaceutical Use

Disinfection (2) UV
1. 2. 3.

UV does not sterilize Flow rate critical Post-irradiation recontamination may be an issue

4.

Lamps have finite life

XO2 Halogen Formaldehyde
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Other chemicals
1.

2.
3.

Module 2, Part 2: Water purification engineering

UV Technology : Electromagnetic Spectrum

Water for Pharmaceutical Use

Visible Infrared

Gamma rays X Rays U.V.

10-10 Wavelength(m)

10-7

10-6

10-4

10-3

Ultraviolet radiation
Ultra short Short UV-C
100 Wavelength (nm)
Module 2, Part 2: Water purification engineering Slide 23 of 25
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Medium UV-B
280

Long wave UV-A

315 400

200

U. V. Technology

Water for Pharmaceutical Use

Relative intensity

185 254 313 Emission of a low pressure mercury lamp.

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Wavelength (nm)

Germicidal Action

Water for Pharmaceutical Use

100% 80% 60% 40% 20% 0% 240 260 280 300 320
254nm

Module 2, Part 2: Water purification engineering

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UV Technology (185 + 254 nm)

Water for Pharmaceutical Use

Conversion of traces of organic contaminants to charged species and ultimately CO2 (185 + 254)

Limited destruction of microorganisms and viruses (254)

Limited energy use Easy to operate

Polishing technique only: may be overwhelmed if organics concentration in feed water is too high. Organics are converted, not removed. Limited effect on other contaminants Good design required for optimum performance.

Module 2, Part 2: Water purification engineering

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Contaminants Removal

Water for Pharmaceutical Use

CONTAMINANT IONS ORGANICS PARTICLES COLLOIDS BACTERIA VIRUSES GASES STILL DI RO UF MF AC

Module 2, Part 2: Water purification engineering

UV : converts organic molecules to CO2 or charged molecules

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Water for Pharmaceutical Use

Sampling (1)
1.
2. 3. 4. 5.

There must be a sampling procedure

Sample integrity must be assured Sampler training Sample point Sample size

Module 2, Part 2: Water purification engineering

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Water for Pharmaceutical Use

Sampling (2)
1.
2. 3.

Sample container
Sample label Sample storage and transport

4.
5.

Arrival at the laboratory

Start of test

Module 2, Part 2: Water purification engineering

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Water for Pharmaceutical Use

Testing - setting specifications for purified water or WFI - (1)
Ph. Eur. pH Cl SO4 NH4 Ca/Mg 5.0-7.0 < 0.5 pass test < 0.2 pass test JP 5.0-7.0 pass test pass test < 0.05 USP 5.0-7.0 Int. Ph. pass test pass test pass test pass test pass test

Nitrates
Nitrites

< 0,2
-

pass test
pass test
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pass test
-

Module 2, Part 2: Water purification engineering

Water for Pharmaceutical Use

Testing - setting specifications for purified water or WFI (2)
Ph. Eur. Conductivity (S/cm) Oxidizable subs. Solids (ppm) TOC (ppm) Heavy metals CO2 pass test < 10 pass test < 10 < 0.5 Slide 31 of 25

JP

USP < 1.3 < 0.5 WHO - EDM

Int. Ph pass test nmt(*) 10 pass test pass test

Module 2, Part 2: Water purification engineering

Water for Pharmaceutical Use

Testing
1.
2. 3.

Method verification
Chemical testing 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
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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 Usually prepared by distillation Storage time should be less than 24 hours Microbial limits must be specified

2. 3. 4.

Module 2, Part 2: Water purification engineering

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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

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Water for Pharmaceutical Use

Pyrogens and endotoxins
1. 2. 3.

Any compound injected into mammals which gives rise to fever is a Pyrogen Endotoxins are pyrogenic, come from Gram negative bacterial cell wall fragments 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

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Water for Pharmaceutical Use

Suggested bacterial limits (CFU /mL)
Sampling location Raw water Post multimedia filter Target 200 100 Alert 300 300 Action 500 500

Post softener
Post activated carbon filter Feed to RO

100
50 20

300
300 200

500
500 500

RO permeate
Points of Use

10
1

50
10
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100
100

Module 2, Part 2: Water purification engineering