WATER FOR PHARMACEUTICAL USE

PRINCIPLES
WATER is the most sensible utility for pharmaceutical production

Like any starting material, water must conform to Good Manufacturing Practices norms It must be potable as a minimum and comply with guidelines for drinking-water quality Water has potential for microbial growth Production and distribution systems must be properly validated Specifications and periodic testing is required Water for parenteral use may easily be contaminated with pyrogens or endotoxins

GUIDELINES
WHO USP

FDA

+ Ph. Eur.

GRADES OF PHARMACEUTICAL WATER

Purified Water (USP / JP / EP) Highly Purified Water (EP) Water For Injection (USP / JP / EP) + Water types for special applications (API, dialysis, inhalation, QC, etc.)

QUALITY REQUIREMENTS PW, HPW, WFI

Purified Water
Parameter TOC Conductivity Conductivity Nitrates (NO3) Heavy metals Aerobe Bacteria Bacteria Endotoxins Unit ppb C S/cm @ 20C S/cm @ 25C ppm ppm as Pb CFU/ml EU/ml EP(bulk) 500 4.3 -- 0.2 0.1 100 --USP(bulk) 500 -- 1.3 ---- 100 ---

Water for Injections

Parameter TOC Conductivity Conductivity Nitrates (NO3) Heavy metals Aerobe Bacteria Bacteria Endotoxins Unit ppb C S/cm @ 20C S/cm @ 25C ppm ppm as Pb CFU/100 ml EU/ml EP(bulk) 500 1.1 -- 0.2 0.1 10 0.25 USP(bulk) 500 -- 1.3 ---- 10 0.25

Highly Purified Water

Parameter TOC Conductivity Conductivity Nitrates (NO3) Heavy metals Aerobe Bacteria Bacteria Endotoxins Unit ppb C S/cm @i 20C S/cm @i 25C ppm ppm as Pb CFU/100 ml EU/ml EP(bulk) 500 1.1 -- 0.2 0.1 10 0.25 USP(bulk) n.a. n.a. n.a. n.a. n.a. n.a. n.a.

TYPES OF WATER IN PHARMACEUTICAL INDUSTRY

PURIFICATION OF RAW WATER

WHY PURIFY RAW WATER?

A water supply is never totaly reliable
l l l l l

Although often reasonably pure, it is always variable Seasonal variations may occur in water Some regions have very poor quality water Necessity to remove impurities to prevent product contamination Necessity to control micro-organisms to avoid product contamination

CONTAMINANTS OF WATER (1)

There is no pure water in nature, as it can contain a large number of unacceptable contaminants Contaminant groups: Inorganic compounds Organic compounds Solids Gases Micro-organisms Treatment depends on waters chemistry and contaminants, influenced by: Rainfall Erosion Pollution Dissolution Evaporation Sedimentation Decomposition

CONTAMINANTS OF WATER (2)

Problems with minerals
Calcium and magnesium Iron and manganese Silicates Carbon dioxide Hydrogen sulfide Phosphates Copper, aluminium Heavy metals, such as arsenic, lead, cadmium Nitrates

Suspended materials
Silt, clay and suspended materials (cause turbidity) Colloids (generally eliminated during first step of purification) Silicates (source of concern in purification))

Micro-organisms Biofilm

Algae, Protozoa Bacteria (notion of objectionable micro-organisms)

Pseudomonas Gram negative, non-fermenting bacteria Escherichia coli and coliforms

BIOFILM FORMATION
Free swimming aquatic bacteria use polymucosaccharides to colonise surfaces then evolve, which shed micro-colonies and bacteria. The bio-adhesion gives to micro-organisms advantages and competitivity compared to micro-organisms in suspension The biofilm is a vector of colonisation by releasing micro-organisms and bacterial derivates (endotoxins, ) This natural process is influenced by Liquid media characteristics Micro-organism type Support material

SOURCES OF RAW WATER

Rain water Surface or ground water Well or borehole Municipal or civil tap water Purchased in bulk

WATER PRE-TREATMENT COMPLEX

External raw water storage

Pretreatment room

WATER TREATMENT

Pre-treatment steps Primary filtration as multi-media filter, activated carbon filter (removal of suspended material, silicates, etc.)

Chlorination / dechlorination

Coagulation or flocculation (removal of colloids, etc.) Desalination Softening

CHLORINE REMOVAL
ACTIVATED-CARBON (AC) FILTRATION OR BISULPHITE

1. 2. 3.

AC removes chlorine but bacteria can then grow AC filtration can remove organic impurities Bisulphite leaves sulphate residues but is antimicrobial AC gets saturated, CANNOT be backwashed, should be replaced or steamed

4.

PRETREATMENT SCHEMATIC DRAWING

Excess water recycled from deioniser Float operated valve Air filter spray ball

To water softener & DI plant

Activated carbon Sand filter filter

Water is kept circulating

Raw water in

break tank

Centrifugal pump Air break to drain S trap to sewer

Cartridge filter 5 micrometers

WATER SOFTENER SCHEMATIC DRAWING

By-pass valve

Soft" water for further process

Brine and salt tank

Zeolite water softener exchanges Ca and Mg for Na Brine

Hard" water in drain

WATER HARDNESS
Water hardness classification mg/L or ppm as CaCO3

Soft Moderate Hard Very hard

0-60 61-120 121-180 > 180

German degrees (dH) Calcium oxyde French degrees (f) Calcium carbonate .

FURTHER WATER PURIFICATION STAGES

Further water treatment purification stages downstream of the pre-treatment system Filtration Disinfection De-ionization and / or Reverse osmosis Electro-deionization Distillation or ultra-filtration

ION EXCHANGE BEADS

Ion exchange beads are typically constructed of a polymeric resin or gel with an average diameter of 0.3 to 1.2 millimeters. The beads can have either cationic or anionic functional groups attached to the surface.

Strong Acid Resins contain functional groups of R-SO3H on the polymeric resin Weak Acid Resins contain functional groups of R-COOH Strong Base Resins contain functional groups of R-OH Weak Base Resins contain functional groups of R-NH3

STRONG ACID CATIONIC RESIN

Typical Cations Na+ Ca2+ Mg2+ Polymeric Resin
R-SO3-H

K+ Metals Cu2+ Fe2+ Zn2+

DE-IONIZER PRINCIPLE
R+OH- + Na+ClR H + Na OH
+ + -

R+Cl- + Na+OHR-Na+ + H+OH-

It should be noted that while deionizers produce water of high ionic quality, they do not remove bacteria or endotoxin (pyrogens). Deionizers lower the quality in terms of bacteria and endotoxin, the resin bed providing an environment helping bacterial proliferation.

TYPICAL DE-IONIZER SCHEMATIC (single beds)

From water softener
Impossible dafficher limage.

HCl

NaOH

6 5 4 3 2 1

6 5 4 3 2 1

Water must be kept circulating

Cationic column

Anionic column

Cartridge filter 5 m

Cartridge filter 1 m

Eluates to neutralization plant Hygienic pump Return to de-ioniser Outlets or storage. Drain line Air break to sewer

Deionizers can operate as single beds and mixed beds

REVERSE OSMOSIS (RO) THEORY

Osmotic Flow
Osmotic pressure

Osmotic Balance

Water

Salt solution

Water

Salt solution

Semi-permeable membrane

Semi-permeable membrane

REVERSE OSMOSIS (RO) THEORY

Reverse Osmosis
Pressure

If a pressure higher than the osmotic pressure is applied on the concentrated solution, the flow will be reversed. Only water from the concentrated solution will be pressed through the membrane. Membrane Material Cellulose Acetate Polyamide, Polysulfone Working Conditions Pressure 10 60 bar Temperature 5 25 C

Water

Salt solution

Semi-permeable membrane

TYPICAL 2-STAGE RO SCHEMATICS

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

Branch

1st stage reject concentrate

First stage filtrate feeds second stage RO with . excess back to 1st stage buffer tank Air break to sewer Second stage RO cartridge

2nd stage buffer tank

High pressure pump

Cartridge filter 1 m

Hygienic pump

Second stage RO water meets Pharmacopoeia standards

Water returns to 1st stage buffer tank Outlets or storage

USE OF REVERSE OSMOSIS

Advantages Less chemical handling than ion exchange (IE) More effective microbial control than ion exchange Integrity test possible Removes most of organic and non-organic contaminants Less energy consumption than distillation Disadvantages Water consumption higher than IE unless waste-water is re-used Danger of microbial growth on membrane Sterilization/sanitization with steam not possible No removal of dissolved gases Working at high temperature (>65 C) only possible with certain types of membrane Many uses Purified water Feeding of distillation units or ultra-filtration units Water for Final Rinse Water for Injections (if and where permissible)

REVERSE OSMOSIS

ELECTRO-DEIONIZATION

ELECTRO-DEIONIZATION

EDI can be used after 2nd pass RO or instead of it

ELECTRO-DEIONIZATION
Before being fed into the EDI module the permeate produced by the reverse osmosis system is divided into three sub-streams. EDI feed water is passed through the diluate chambers filled with ion exchange resin. Through the action of the electric field, the anions migrate through the resin bed in the direction of the anode. As a result they pass through the anion-permeable membrane and arrive in the adjacent stream of concentrate. The cations migrate through the resin bed in the direction of the cathode, pass through the cationpermeable membrane, and so likewise enter the stream of concentrate. With the concentrate stream, the ions are expelled from the module. The electrolyte stream flushes out the gases that are created at the electrodes, along with the ions, and carry them cut of the module As a result of the electrical voltage, water splitting occurs in the resin bed of the diluate chamber. The H+ and OH- ions that are needed for the regeneration of the exchange resin are created. These regenerate the resin bed on an ongoing basis. In this way continuous operation can be maintained, without any need to switch oft the system for regeneration purposes.

ULTRA-FILTRATION

Can be used for WFI or for Water for Final Rinsing for parenteral manufacturing (= Highly Purified Water), if permitted Removes organic contaminants, such as endotoxins, less efficient in removing ions Operation at 80C, and sterilization at 121C

FILTRATION

TYPICAL PW STORAGE AND DISTRIBUTION SCHEMATIC

Flowmeter

Feed Water from DI or RO

Hydrophobic, heated air filter & burst disc

Optional filter 0,2 m Spray ball

UV light Points of use

Water must be kept circulating

Heat Exchanger Hygienic pump

Air break to drain

Flowmeter controls speed of pump, to guarantee sufficient flow speed of water in the loop (turbulent flow, to prevent build-up of biofilms)

TYPICAL PW STORAGE AND DISTRIBUTION SCHEMATIC

Flowmeter

Feed Water from DI or RO

Hydrophobic, heated air filter & burst disc

Optional filter 0,2 m Ozone generator

UV light Points of use

Water must be kept circulating

Hygienic pump

Air break to drain

Flowmeter controls speed of pump, to guarantee sufficient flow speed of water in the loop (turbulent flow, to prevent build-up of biofilms)

DISTRIBUTION LOOPS

TYPICAL PW GENERATION AND STORAGE INSTALLATION

PURIFIED WATER
is obtained from drinking water (in accordance with the relevant national standards) contains no added substances is obtained by a suitable process requires frequent sanitization and microbiological monitoring to ensure quality

HIGHLY PURIFIED WATER

USP and JP allow for WFI to be produced by either distillation or membrane processes (e.g. RO/EDI/UF) Ph Eur allows only using distillation Highly Purified Water meets the quality criteria for WFI but is produced through less expensive membrane processes HPW intended for use in the preparation of products where water of high biological quality is needed, except where WFI is required.

WATER FOR INJECTIONS (WFI)

meets all requirements for Purified Water, with stricter microbial limits is obtained by a suitable process USP: distillation or equivalent or superior purification process
Ph Eur: distillation only JP: distillation or RO or UF

meets bacterial endotoxine requirements is prepared using suitable means to minimize microbial growth. Is stored and distributed hot, with Point Of Use heat exchangers, where necessary

PH.EUR.

USP

USP SPECIFICATIONS: PW >< WFI

PW* (Purified Water) Water conductivity and pH Total Organic Carbon (TOC) Aerobic Microbial Contamination Endotoxin content Production Methods < 2.1 S/cm pH 5-7 0.5 ppm < 100 CFU/ ml Not Specified Obtained by suitable process WFI (Water for Injections) < 2.1 S/cm pH 5-7 0.5 ppm < 10 CFU/100 ml < 0.25 EU/ml Obtained by suitable process and purified by Distillation or RO (or UF)

CFU=Colony Forming Units

SPECIFICATIONS PW - WFI COMPARISONS

CONDUCTIVITY
Electrical Conductivity is the ability of a solution to transfer (conduct) electric current. It is the reciprocal of electrical resistivity (ohms). Conductivity is used to measure the concentration of dissolved solids, which have been ionized in a polar solution such as water. The unit of measurement commonly used is one millionth of a Siemens per centimeter (micro-Siemens per centimeter or S/cm) Temperature plays a role in conductivity, and because ionic activity increases with increasing temperature, conductivity measurements are referenced to 20 C or 25C (depend ing on the pharmacopoeia)

TOTAL ORGANIC CARBON

Introduction of organic matter into water systems occurs not only from living organisms and from decaying matter in source water, but also from purification and distribution system materials. A relationship may exist between endotoxins, microbial growth, and the development of biofilms within distribution systems, and thus between TOC concentrations and the levels of endotoxins and microbes. Virtually all TOC analyzers measure the CO2 formed when organic carbon is oxidized and/or when inorganic carbon is acidified. Oxidation is performed either through Pt-catalyzed combustion, by heated persulfate, or with a UV/persulfate reactor. Once the CO2 is formed, it is measured by a detector: either a conductivity cell (if the CO2 is aqueous) or a non-dispersive infrared cell (after purging the aqueous CO2 into the gaseous phase) TOC is an important tool in cleaning validation. Glassware cleaning is important, as TOC is a very sensitive test

WFI COMPLETE PROCESS

Distillation system Reverse Electroosmosis deionisation Tank

Feed water

Components used: Heat Exchangers Pumps Valves Installation material Tank Equipment

Tank WFI loop

Point of Use

Point of Use

PRODUCTION OF WATER FOR INJECTIONS

Single-effect distillation
simple distillation, single effect vapour compression, thermo compression

Multi effect distillation

multiple effect stills

Clean steam generators

used where steam can come into contact with product contact surfaces, e.g. sterilization-in-place (SIP)

DISTILLATION SYSTEMS
The pharmaceutical still chemically and microbiologically purifies water by phase change and entrainment separation. In this process, water is evaporated producing steam. The steam disengages from the water leaving behind dissolved solids, non-volatiles, and high molecular weight impurities. However, low molecular weight impurities are carried with water mist / droplets, which are entrained in steam. A separator removes fine mist and entrained impurities, including endotoxins. The purified steam is condensed into water for injection. Distillation systems are available to provide a minimum of 3 log10 reduction in contaminants such as microorganisms and endotoxins. Three designs are available - single effect (SE), - multi-effect (ME) - vapour compression (VC).

DISTILLATION SYSTEMS
In a multi effect still, purified steam produced in each effect is used to heat water and generate more steam in each subsequent effect. Energy efficiency increases with each effect added. In a vapour compression still, steam generated by the evaporation of feedwater is compressed and subsequently condensed to form distillate VC stills require water softening for removing calcium and magnesium as minimum. ME stills require higher water quality. Ion exchange or reverse osmosis units are usually used as pre-treatment. All distillation units are susceptible to scaling and corrosion.

MULTI-EFFECT SYSTEM

MULTI-EFFECT SYSTEM

Water is only distilled once, whatever the number of effects

WATER FOR INJECTIONS

VAPOUR COMPRESSION SYSTEM

Thermocompressor

WFI STORAGE AND DISTRIBUTION SCHEMATIC

Feed Water from Distiller

Hydrophobic air filter & burst disc Flowmeter Spray ball

Water must be kept circulating

Points of Use

UV light

Heat Exchanger Hygienic pump Air break to drain

Flowmeter controls speed of pump, to guarantee sufficient flow speed of water in the loop (turbulent flow)

GMP EXPECTATIONS
Issues such as quality of installation, sampling and testing procedures, operating and maintenance procedures, record keeping, etc. often have greater significance than the particular technologies selected to purify and distribute the water.

Source: ISPE Baseline Guide

GMP CONSIDERATIONS FOR WATER SYSTEMS

Microbial Design Considerations for system and loop
Continous Flow - system not in service, re-circulation line should be included Turbulent Flow / Velocity - Reynolds number >4000 Frequent Sanitization Sampling valves: between each purification step operating temperature Continuous Microbial control Methods: - Elevated or reduced temperatures - Ozonation of distribution systems Proper Slope/ Drainability fully drainable for systems that will never be sanitized allow for draining of equipment and associated piping Finishes Product contact, less than Ra 0.8 m Deadlegs: 6-D Regulation as a minimum Cleaning / Passivation Critical Instrument Review: -Calibration; Conductivity and Temperature -Temperature at coldest point by hot water sanitization

VALVES
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

DIAPHRAGM VALVES

DIAPHRAGM VALVES

Principle design:

DIAPHRAGM

VALVE BODY

FUNCTION OF DIAPHRAGM VALVE

SHELL & TUBE HEAT EXCHANGER

Sanitary shell & tube heat exchanger where the product flow goes through several seamless, electropolished tubes with the service media on the shell side.

DOUBLE TUBE EXCHANGERS

To prevent cross-contamination, two tube sheets are connected at both ends with the tubes expanded into the tube sheet.

In case of leakage

POINT-OF-USE COOLER

A module installed as a point of use cooler

POINT OF USE INSTALLED IN SUBLOOP

Here, sanitization is accomplished by circulating hot water from the loop, through the point of use exchanger to the main loop. The operation can be facilitated by installing a block valve at the return of the main loop. The initial draw of point of use water would be diverted to drain.
Restriction Orifice

This subloop leads to added pressure drop in the main loop which leads to the use of a larger circulation pump

Hot Loop

Hot Loop

Coolant

Point of Use

INSTALLATION MATERIAL - REQUIREMENTS

Surface finish Stainless steel material Dimensions and Tolerances Tubes and fittings standards Traceability (according to EN 10204, MR) Welded / Seamless Orbital automatic welding

PIPING MATERIALS
PVC Polyvinyl Chloride PE Polyethylene UHMW PE Ultra high molecular weight PE CPVC Chlorinated Polyvinyl Chloride PP Polypropylene (Natural or Gray) PVDF Polyvinylidene Fluoride HP PVDF High Purity PVDF Teflon -various forms PTFE Polytetrafluoroethylene ECTFE Ethylene chlorotrifluorethylene (Halar) ETFE Ethylene tetrafluoroethylene CTFE Chlorotrifluorethylene PFA Perfluoroalkoxy resin PEEK Poly Ethyl Ethyl Ketone 316L SS stainless steel

STEEL
American Society for Testing and Materials American Iron and Steel Institute

STAINLESS STEEL MATERIALS

Material Designation DIN 1.4404 1.4435 1.4571 1.4401 1.4539 AISI 316L 316L 316Ti 316 904

Low-Carbon-steel

Titanium-stabilized V4A (old German Classification) Alternative material for rouging avoidance (?)

Today we see mainly low carbon steel in use for high purity water systems, In previous times steel grades such as 1.4571 and 1.4401 had been used on a more frequent basis It is recommended to use only one material for better welding

PIPING MATERIALS - 316L SS

Not suitable if ppt ion limitations are required Not used in high purity laboratory water applications. Will rouge under most conditions especially with hot, high quality water. Insulation required

GASKET MATERIAL

EPDM Rubber Viton Hypalon White FDA Silicone Teflon encapsulated viton Gore-tex (expanded teflon) Kalrez (elastomeric teflon)

PIPES SIZES
Securing turbulent flow conditions Pipeline sizing DIN 11850
(external diameter) mm x (wall thickness) mm

Minimum pass At 20 C m/s 2,5 1,6 1,0 0,7 0,5 m/h 0,7 1,1 1,9 2,7 3,6 m/s 0,9 0,5 0,3 0,2 0,2 At 85 C m/h 0,2 0,4 0,6 0,9 1,2

DN 10 DN 15 DN 25 DN 40 DN 50

13 x 1,5 19 x 1,5 29 x 1,5 41 x 1,5 53 x 1,5

SURFACE QUALITY
Besides the materials of construction the quality of media contact surfaces is one of the main criteria for cleanability, resistance and interactions between media and surface Well defined grinding regime and cold drawn tubes allow to reach a surface roughness of Ra 0,8 m without problems. Well polished stainless steel surfaces and specially treated tubes can get down to Ra 0,4 m Another enhancement can be reached by electropolishing of surfaces. This allows to get down to a surface roughness of Ra 0,2 m. There is no significant improvement of microbiological water quality known using materials with a surface roughness Ra 0,8

Ra-VALUE
The average surface height deviation from the mean, measured with a profilometer Result is a length measurement

Avg. dev.
R a

Mean

Material surfaces

Attached bacteria
Avg. dev.
R a

Identical Ra-value not necessarily identical cleanability !!!

PASSIVATION
Passivation is the removal of exogenous iron or iron compounds from the surface of stainless steel by means of a chemical dissolution, most typically by a treatment with an acid solution that will remove the surface contamination, but will not significantly affect the stainless steel itself, for the purpose of enhancing the spontaneous formation of a thin (1 m) protective, transparent passive film (chromium oxide). The passivation process removes "free iron" contamination left behind on the surface of the stainless steel from machining and fabricating. These contaminants are potential corrosion sites that result in premature corrosion and ultimately result in deterioration of the component if not removed

ELECTROPOLISHING
Enhanced Surface Finish Corrosion Resistance (Passivated Surface) Removes Polishing Compounds High Lustre Appearance An electropolished surface will be smoother than a mechanically polished surface with the same Ra Electropolishing removes free iron from the surface, increasing the Cr/Fe ratio at the surface, thus enhancing the passive layer Electropolishing reveals surface defects for simple visual inspection.

ORBITAL WELDING

ORBITAL TUNGSTEN INERT GAS WELDING

Principle
During the weld the material remains stationary while the tungstene (wolfram) automatically travels around the tube The power supply controls the welding current, pulsation rate and travel speed Possible to change the welding parameters during the welding Possible to print real welding parameters

ORBITAL TUNGSTEN INERT GAS WELDING

Controlled heat input through programmable sectors. Constant weld speed. Ensured gas coverage with controlled N2 and/or H2 content. Exact electrode distance = constant current and voltage. Easy access at hard to reach points. Insensitive to draught and wind.

WELDING DOCUMENTATION
1 17 2 16 15 5 4 3

Essential for qualification

13 12 11 8 10 9 14 6

Marking of each single weld in order to maintain traceability to welding documentation

WELDING CONTROL BY ENDOSCOPE

WELDING REQUIREMENTS - SUMMARY

Tubes must have appropriate chemical composition Tolerances on diameter and thickness must be very small Tube / fitting ends must be clean with no gap between Tubes should be supplied in protected form Welders must be qualified Welding of stainless steel must be separated from welding with ordinary steel

DISINFECTION WATER SYSTEMS

Heat One of the most reliable methods of disinfection of water systems

Ozone Produced easily Leaves no residue

UV UV does not sterilize Flow rate critical Post-irradiation recontamination may be an issue Lamps have finite life

Other chemicals XO2 Halogen Formaldehyde

CHEMICAL SANITIZATION
Efficient and accepted method Low Investment (Dosing unit for chemicals) Automatic sequence (only for verification of chemical substance)
filter 90 m Raw water Dosing pump Circulation Piping Reverse Osmosis Softener Safe filter 5 m Heater Exchanger Pump

Dosing pump

Purified Water tank EDI SEPTRON EDI Concentration Tank

HOT WATER SANITIZATION

In-line HE (electrical or Steam) brings system water to > 80 C

filter 90 m Rawwater

Softeners

Safe filter 5 m

Pump Heater Exchanger

Reverse Osmosis Circulation piping

Re-circulation incl. piping from and to storage tank Automatic sequence

Purified Water tank EDI SEPTRON EDI Concentration Tank

HOT WATER SANITIZATION

Efficient and accepted method No chemicals handling or storage Easy documentation (Recorder print-out) Rapid operational start after sanitization No chemical substances to rinse out, no polluted drain/waste water

C 100 90 80 70 60 50 40 30 20 10 0 0:00

Temperature Profile

Sanitizing Start heat-up Start

System ready

0:30

1:00

1:30

2:00

2:30

3:00

3:30

4:00

4:30

Time [h]

OZONISATION
Ozone is very reactive but also unstable. It cannot therefore be stored and has to be produced where and when it is needed. Ozone is produced from oxygen-containing gases in ozone generators by means of a silent electrical discharge. A high voltage is applied between two concentrically arranged electrodes. The electrodes are separated from each other by a dielectric and two discharge chambers, through which gas flows. Some of the oxygen molecules in the input gas break down in the electric field and immediately attach themselves to free oxygen molecules, forming ozone

OZONE EFFICIENCY

Sanitizing generally at 25ppb

Hoffmann-La Roche (Swiss Pharma 1983)

OZONE OR HOT WATER SANITIZATION

Ozone - continuously
Microbiological behaviour in ambient purified water loops with ozone ( ~25 ppb)
130 120 110 100
100 130

Hot Water- periodic

Microbiological behaviour in ambient purified water loops with periodic hot water sanitisation
Action level purified water
120 110

Action level purified water

Germ count [ cfu/ ml]

90 80 70 60 50 40 30 20 10 0
1

Germ count [ cfu/ ml]

90 80 70 60 50 40 30

Continuous sanitisation by ozone < 10 cfu/ml

Periodic sanitisation by hot water (>80 C) Accepted contamination

Action level water for injection

20 10 0
1

Operation time

Operation time

SANITISATION OF COLD DISTRIBUTION SYSTEMS:

OZONE OR HOT WATER ?
Criterion
Microbiological safety

Ozonization (10 100 ppm)

Very high - Reduction of CFU - Reduction (removal) of TOC - Reduction of endotoxins Very high Because of continuous circulation, even during water consumption High Ozone generator, static mixer, UV-generator (to destroy ozone before entering the distribution loop), ozone monitor, (ozone monitor for the environment) Low Electricity for ozone and UV generator High - Exchange of UV-Radiator every 10.000 h - Calibration of sensors every year - Change of electrolyte every two years Very high No interruption necessary during production or consumption Low Selection of suitable gasket materials (elastomers) required Low

Hot Water Sanitisation

High - Reduction of CFU

Efficacy

High But only if no consumption of water is planned Relatively low Heat exchanger and insulation

Installation costs

Running costs

High For periodic heating and cooling Low - Change of gaskets (periodically)

Maintenance

Process Continuity Material Stress Space requirement

Conditional Interruption necessary for sanitisation Medium Eventually roughing Low

UV DISINFECTION
One of the most effective alternative water disinfection process available is ultraviolet light (UV). UV disinfection mimics the sun's natural behavior: that is, ultraviolet energy destroys the ability of dangerous microorganisms to multiply, rendering them harmless to humans and the environment. It falls to the left of visible light with higher energy levels and wavelengths between 100 and 400 nm. One of the most effective wavelengths and the one most often used for disinfection is at 254 nm. A watertight quarz tube surrounds each lamp. The liquid to be disinfected is passed through the quartz tubing. The gas plasma generated in the lamp emits light with a primary wave length of 253.7 nm. This intensive UV light reaches the microorganisms in the water and impacts directly on their DNA.

UV DISINFECTION

WATER TREATMENT GUIDANCE

All water-treatment systems should be subject to:
planned maintenance validation monitoring

Maintenance work should be documented For reliable production, water treatment plants should be:
1. 2. 3. 4. 5.

Designed Constructed Maintained Operated within design limits Controlled to prevent microbial growth

WATER QUALITY MANUAL

The manual should contain: Specification for each system element Standard procedures for use System changes Routine and non-routine maintenance Investigations and corrective action Validation studies Chemical and microbiological specifications Sampling instructions Test procedures Responsible persons Training requirements The manual should show: Pipelines Non-return (or check) valves Breather points Couplings Pipe slopes Velocities Valves Sampling points Drain points Instrumentation Flow rates

DESIGN DOCUMENTS
Functional Specification Mechanical Engineering
P&ID Component list Assembly Drawings

Electrical Schematics
HDS, Hardware Design Specification Wiring Diagram Control Cabinet list Software & Program SDS (Software Design Specification) Functional Logics

PROJECT OVERVIEW
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 Kick-off meeting Design Design Approval (DQ) Purchasing Receiving Inspections Manufacturing Welding Inspection Software Review (office tests) Commissioning & Start-up 1 (skid-mounted equipment) Internal pre-FAT Factory Acceptance Tests Shipments Installations on site (electrical / mechanical) Commissioning & Start-up 2 (complete systems) Site Acceptance Tests IQ / OQ Training Hand Over

V-MODEL

INSTALLATION QUALIFICATION
1. Documentation : Drawings, P&IDs, isometry Certificates calibration Technical Datasheet and drawings components Materials certificates (Mill tests) Operation and maintenance manuals, list of spare parts Passivation report Welding reports, qualification welders, welding samples, analytical report inert gas Endoscopies and X-Ray reports SOPs Filters certificates Software (version) 2 Verification of critical components: Valves Filters : cartridges and housings Connections tri-Clamp Components of installation: softener, carbon filter, chemicals tanks and pumps, UV, RO, intermediate tanks, distribution system, etc. 2A) Verification of non critical components : From water entrance until RO 3. Instrumentation A) Critical : Conductivity (loop and tank) Flowmeters TOC Temperature Pressure in loop B) Non critical : Hardness Level control Local pressures 4. Specific tests Pre-treatment : Leaks, correctness of installation LOOP: Roughness Slopes, angles valves Dead legs Passivation Cleaning Identification elements Verification of connections: Electricity, compressed air, feedwater

OPERATION QUALIFICATION
Calibration (control instruments and instruments used in tests Emergency stop Test for electrical breakdown SOPs (approved) Training Operating sequences Operation pump(s) Alarms: simulated and non simulated (set-points) I/O (input output) Interlocks Tests for water quality: Pre-treatment and feed-water Test pre-treatment outlet and RO outlet

PERFORMANCE QUALIFICATION (PQ)

TOC Conductivity, chemical tests Bioburden (total microbial count, including objectionable organisms) Endotoxins (for WFI)

Tests phase 1 (WHO example: 2 4 weeks)

Undertake chemical and microbiological testing in accordance with a defined plan. Sample the incoming feed-water daily to verify its quality. Sample after each step in the purification process daily. Sample at each point of use and at other defined sample points daily. Develop appropriate operating ranges. Develop and finalize operating, cleaning, sanitizing and maintenance procedures. Demonstrate production and delivery of product water of the required quality and quantity. Use and refine the standard operating procedures (SOPs) for operation, maintenance, sanitization and troubleshooting. Verify provisional alert and action levels. Develop and refine test-failure procedure

Tests phase 2 :
A further test period of 24 weeks should be spent carrying out further intensive monitoring while deploying all the refined SOPs after the satisfactory completion of phase 1. The sampling scheme should be generally the same as in phase 1. Water can be used for manufacturing purposes during this phase. The approach should also: demonstrate consistent operation within established ranges; and demonstrate consistent production and delivery of water of the required quantity and quality when the system is operated in accordance with the SOPs.

Tests phase 3 :
Phase 3 typically runs for 1 year after the satisfactory completion of phase 2. Water can be used for manufacturing purposes during this phase which has the following objectives and features. Demonstrate extended reliable performance. Ensure that seasonal variations are evaluated. The sample locations, sampling frequencies and tests should be reduced to the normal routine pattern based on established procedures proven during phases 1 and 2.

CONTINUOUS SYSTEM MONITORING

After completion of phase 3 of the qualification program for the WPU system, a system review should be undertaken. Following this review, a routine monitoring plan should be established based on the results of phase 3. Monitoring should include a combination of online instrument monitoring of parameters such as flow, pressure, temperature, conductivity and total organic carbon, and offline sample testing for physical, chemical and microbiological attributes. Offline samples should be taken from points of use and specific sample points. Samples from points of use should be taken in a similar way to that adopted when the water is being used in service. Tests should be carried out to ensure that the appropriate pharmacopoeia specification has been met (in accordance with the related marketing authorization), and should include, as appropriate, determination of conductivity, pH, heavy metals, nitrates, total organic carbon, total viable count, presence of specific pathogens and endotoxins. Monitoring data should be subject to trend analysis. Any trend towards frequently exceeding action limits should precipitate a review of the qualification status of the system Maintenance of water systems WPU systems should be maintained in accordance with a controlled, documented maintenance program that takes into account the following: defined frequency for system elements; the calibration program; SOPs for specific tasks; control of approved spares; issue of clear maintenance plan and instructions; review and approval of systems for use upon completion of work; and record and review of problems and faults during maintenance.

CONTINUOUS SYSTEM MONITORING

Points of Use The quality of water procured from the user point configurations and sample points

Point of Return The quality of water the piping system distributes

Point of Distribution The quality of water the system design produces Post-treatment

Pump

CLEAN STEAM

STEAM STERILISATION

Water, in its gaseous state, is invisible, but a carrier of energy and humidity It is quite cheap and appreciated in the pharmaceutical industry for Heating and maintaining temperature Humidification Sterilisation of products and materials

Vaporisation Water Condensation Steam

STEAM STERILISATION

Steam sterilization is considered the elective method by all Pharmacopeias, Standards and Guidelines. Accordingly, it must be preferred, unless problems of incompatibility of the material to be sterilized with the temperature, humidity or pressure of the steam make it indispensable to use another method.

EMEA Decision tree

STEAM STERILISATION

STEAM RELEASES A LOT OF ENERGY AT A CONSTANT TEMPERATURE

When water vapor condenses, it releases a very large amount of heat at the constant temperature of condensation. 1 kg of steam that condenses at 121 C (becoming ho t water at 121 C) in fact releases 525 kilocalories. Vice versa, 1 kg of hot water, by cooling by 1 C ( for example from 121 to 120 C), releases only 1 kilocalorie.

ANOTHER ADVANTAGE OF STEAM

One mole of water vapor (constituted by 18 g of water) occupies, at 121 C and 2.05 bar, a volume of approximately 15 liters. When it condenses at 121 C, it is converted into 18 ml of water. In practice, the contraction in volume is almost by 1,000 to 1. This means that other steam will spontaneously reach the material to be treated.

STEAM STERILISATION

COMBINATION OF TEMPERATURE + HUMIDITY

The steam must make contact with the microorganisms to be destroyed. This is indispensable, since it is the combination of temperature + humidity that produces the sterilizing effect of steam. Contact can be: Direct (e.g. a surgical instrument, sterilized loose or packaged in a steampermeable package, processing equipment, e.g. a vessel). or Indirect (e.g. an aqueous solution contained in a glass ampoule).

STEAM STERILISATION
SATURATED STEAM Saturated water vapor must be used to sterilize. A vapor is saturated when it is in equilibrium with its own liquid form at the temperature being considered. In practice, dry saturated water vapor does not exist. What is usually used is moist steam, and this is indeed an assurance that it is saturated and not superheated. What matters is that the amount of entrained condensate is small. Steam with a titer of 0,95 is constituted by 95 parts by weight of steam plus 5 parts by weight of condensate at the same temperature as the steam. Steam with a titer of less than 0.90 should not be used because it would wet the load excessively. WATER STATE CHART In the temperature/pressure diagram of water, saturated steam is represented by a slightly curved line. This means that for saturated steam there is a one-to-one correspondence between temperature and pressure. If one chooses the temperature of the saturated steam, its pressure is automatically determined, and vice versa. 121 C produce a pressure of 2.05 abs bar and 3.04 abs bar give a temperature of 134 C.

STEAM STERILISATION

WITHOUT DIRECT STEAM-MICROORGANISM CONTACT THERE IS NO STERILIZATION If a surgical instrument is contained in a hermetic metallic box, or if a solution contained in the ampoule is an anhydrous oily solution, no sterilization occurs, or rather only the outer surfaces of the box and of the ampoule are sterilized. THE AIR INSIDE THE CHAMBER WHEN STERILIZATION BEGINS MUST BE ELIMINATED Air is approximately 1.7 times denser than steam in equal temperature/pressure conditions. If the air is not eliminated completely, it stratifies in the lower parts of the chamber and of any empty open containers whose mouth faces upward. This prevents the correct sterilization conditions from being achieved.
Closed

Gravity Vacuum

Air

Air Air

Open Open

Open Open Steam Steam Steam Steam

Closed

STEAM STERILISATION CYCLES

Selection of cycle depends on product / good to be sterilised (pre-vacuum, sterilisation, cooling, etc.)

STEAM QUALITIES
Steam generated may carry droplets of the feed water which might contain ions, other dissolved materials and particles, volatile compounds, pyrogenic material (endotoxins) and so on, that may contaminate the sterilized goods. In practice the terminologies plant (process) steam, filtered steam, clean steam and pure steam are often used. Clean steam is often defined as equivalent to pure steam.

Plant (process) steam

Plant (process) steam, also called In-House Steam, refers to steam of undefined quality from a boiler, without further treatment. Boiler additives, iron oxides, feed water contaminants and scales from the boiler or distribution piping system are often present and could contaminate the goods. Some contaminants may be visibly evident, as discoloration of the sterilized goods and sterilizer chamber.

Filtered steam
Filtered steam is plant steam that has passed through a 10-20 m stainless steel filter to remove particles. Colloidal iron from the piping system is difficult to remove and will aggregate after filtering, to show up as particulate iron oxides. At high steam velocities condensate and unevaporated feed water will be forced through the filter. The same problems as seen for plant steam are often encountered but to a lesser extent.

STEAM QUALITIES
Clean Steam
Clean steam is steam derived from a steam generator, preferably of stainless steel, without any separation system. The feed water is usually softened, deionized or reverse osmosis (RO) water, depending on the generator and raw water quality. There is no absolute guarantee that the feed water is free from ions, particles or pyrogens, and there is a risk of such contaminants being carried over in droplets, together with the steam generated. To minimize this contamination the steam can be filtered through a 3-15 m stainless steel filter. At high steam velocities, condensate and unevaporated feed water may also be forced through the filter. For medicinal products that are sterilized in closed containers, clean steam can be used, provided that the sealing system and process have been validated or a reliable leak detection system employed.

Pure Steam
Condensate of Pure Steam is expected to meet the requirements for WFI. This means it should have a low ion content, an endotoxin level below 0,25 IU/ml and a low level of particles. The steam should be produced in a Pure Steam Generator which has a separation system. To separate droplets from the steam, some kind of separation system must also be included. This can be a gravity separation system, a cyclone or a de-mister. Sometimes, combinations are used. Feed water may be softened, RO or deionized water, depending on the generator and raw water quality. Pure steam must be used whenever any item that comes into direct contact with a sterile medicinal product is sterilized

PURE STEAM
Pure Steam Monograph (USP 29)
Pure Steam is water that has been heated above 100 degrees Celsius and vaporized in a manner that prevents source water entrainment. It is prepared from water complying with the U.S. EPA NDWWR, or with drinking water regulations of the EU, Japan or with WHO drinking water guidelines. It contains no added substance. The level of steam saturation or dryness, and the amount of non-condensable gases are to be determined by the Pure Steam application. [Note: Pure Steam is intended for use where the steam or its condensate comes in contact with the article or the preparation. Pure Steam quality is difficult to asses in its vapour form; therefore its condensate is used to test its quality. The process used to collect the condensate for analysis must not adversely impact these quality attributes.] Bacterial endotoxins: (85): The condensate contains less than 0.25 EU/ml. Total organic carbon (643): The condensate meets the requirement. Water conductivity (645): The condensate meets the requirement.

PHYSICAL PROPERTIES OF CLEAN STEAM

Physical properties of clean steam, such as dryness, superheat, noncondensable gases and steam/air homogeneity, will influence the bacterial reduction properties. Steam for sterilization purposes should be dry and saturated. Dryness value > 0,95 (> 0,90) Non Condensable gases < 3,5% Superheat < 25 K The presence of high levels of moisture will lead to excessive amounts of condensate. This, in turn, may cause a temperature lag in areas where the excess has settled. After sterilization it would also be difficult to dry the goods. Superheated steam will remove the moisture from the bacteria present. If micro-organisms are not properly hydrated they become more resistant to heat and require longer sterilization times.

PRODUCTION CLEAN STEAM

STEAM STERILISATION