unistra 03 water 2012 mode de compatibilite

WATER FOR PHARMACEUTICAL USE

WATER is the most sensible utility for pharmaceutical production

• Like any starting material, water must conform to GoodManufacturing Practices norms

• It must be “potable” as a minimum and comply with guidelinesfor 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 withpyrogens or endotoxins

PRINCIPLES

GUIDELINES

WHO

USP

FDA

+ Ph. Eur.

5

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

6

Parameter Unit EP(bulk) USP(bulk)

TOC ppb C ≤≤≤≤ 500 ≤≤≤≤ 500

Conductivity µS/cm @ 20°°°°C ≤≤≤≤ 4.3 ---

Conductivity µS/cm @ 25°°°°C --- ≤≤≤≤ 1.3

Nitrates (NO3) ppm ≤≤≤≤ 0.2 ---

Heavy metals ppm as Pb ≤≤≤≤ 0.1 ---

Aerobe Bacteria CFU/ml ≤≤≤≤ 100 ≤≤≤≤ 100

Bacteria Endotoxins EU/ml --- ---


TOC ppb C ≤≤≤≤ 500 ≤≤≤≤ 500

Conductivity µS/cm @ 20°°°°C ≤≤≤≤ 1.1 ---

Conductivity µS/cm @ 25°°°°C --- ≤≤≤≤ 1.3

Nitrates (NO3) ppm ≤≤≤≤ 0.2 ---

Heavy metals ppm as Pb ≤≤≤≤ 0.1 ---

Aerobe Bacteria CFU/100 ml ≤≤≤≤ 10 ≤≤≤≤ 10

Bacteria Endotoxins EU/ml ≤≤≤≤ 0.25 ≤≤≤≤ 0.25


TOC ppb C ≤≤≤≤ 500 n.a.

Conductivity µS/cm @i 20°°°°C ≤≤≤≤ 1.1 n.a.

Conductivity µS/cm @i 25°°°°C --- n.a.

Nitrates (NO3) ppm ≤≤≤≤ 0.2 n.a.

Heavy metals ppm as Pb ≤≤≤≤ 0.1 n.a.

Aerobe Bacteria CFU/100 ml ≤≤≤≤ 10 n.a.

Bacteria Endotoxins EU/ml ≤≤≤≤ 0.25 n.a.

Purified Water

Highly Purified Water

Water for Injections

TYPES OF WATER IN PHARMACEUTICAL INDUSTRY

PURIFICATION OF RAW WATER

A water supply is never totaly reliable

l Although often reasonably pure, it is always variable

l Seasonal variations may occur in water

l Some regions have very poor quality water

l Necessity to remove impurities to prevent product contamination

l Necessity to control micro-organisms to avoid product

contamination

WHY PURIFY RAW WATER?

There is no pure water in nature, as it can contain a large number ofunacceptable contaminants

Contaminant groups:

• Inorganic compounds• Organic compounds• Solids• Gases• Micro-organisms

CONTAMINANTS OF WATER (1)

Treatment depends on water’s chemistry and contaminants, influenced by:• Rainfall• Erosion• Pollution• Dissolution• Evaporation• Sedimentation• Decomposition

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

CONTAMINANTS OF WATER (2)

Free swimming aquatic bacteria use polymucosaccharides to colonisesurfaces then evolve, which shed micro-colonies and bacteria.The bio-adhesion gives to micro-organisms advantages andcompetitivity compared to micro-organisms in suspension

The biofilm is a vector of colonisation by releasing micro-organismsand bacterial derivates (endotoxins, …)

This natural process is influenced by• Liquid media characteristics • Micro-organism type • Support material

BIOFILM FORMATION

Rain water

Surface or ground water

Well or borehole

Municipal or civil – “tap water”

Purchased in bulk

SOURCES OF RAW WATER

WATER PRE-TREATMENT COMPLEX

Pretreatment room

External raw water storage

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

WATER TREATMENT

CHLORINE REMOVALACTIVATED-CARBON (AC) FILTRATION OR BISULPHITE

1. AC removes chlorine but bacteria can then grow

2. AC filtration can remove organic impurities

3. Bisulphite leaves sulphate residues but is anti-microbial

4. AC gets saturated, CANNOT be backwashed, shouldbe replaced or steamed

Raw water in

« S” trap to sewer

Water is keptcirculating

To water softener &DI plant

PRETREATMENT SCHEMATIC DRAWING

Cartridgefilter

5 micrometers

Activatedcarbon

filter

spray ball

break tank

Air break to drain

Centrifugal pump

Air filter

Floatoperated

valveSand filter

Excess water recycledfrom deioniser

WATER SOFTENER SCHEMATIC DRAWING

Brine

“Hard" water indrain

“Soft" waterfor further process

By-passvalve

Brine andsalt tank

Zeolite watersoftenerexchanges

Ca and Mgfor Na

WATER HARDNESS

Water hardnessclassification

mg/L or ppm

as CaCO3

Soft 0-60

Moderate 61-120

Hard 121-180

Very hard > 180

German degrees (｡dH)

Calcium oxyde

French degrees (｡f)

Calcium carbonate.

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

FURTHER WATER PURIFICATION STAGES

ION EXCHANGE BEADS

Ion exchange beads are typically constructed of a polymeric resin or gelwith an average diameter of 0.3 to 1.2 millimeters.

The beads can have either cationic or anionic functional groups attachedto the surface.

• Strong Acid Resins contain functional groups of R-SO3Hon 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

Polymeric ResinR-SO3-H

Na+

K+

Cu2+

Mg2+

Ca2+

TypicalCations

Metals

Fe2+

Zn2+

R+OH

-+ Na

+Cl

-R

+Cl

-+ Na

+OH

-

R-H

++ Na

+OH

-R

-Na

++ H

+OH

-

DE-IONIZER PRINCIPLE

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)

Deionizers can operate as single beds and mixed beds

Cationic column Anionic column

Hygienic pump

Outlets or storage.

Impossibled’afficherl’image.

HCl NaOH

Eluates toneutralization

plant

Air break to sewer

Drain line

From water softener

Watermust bekeptcirculating

1

2

345

6

1

2345

6

Return to de-ioniser

Cartridgefilter 5 µm


Osmotic Flow

Semi-permeablemembrane

Water Saltsolution

Osmoticpressure

Osmotic Balance

Semi-permeablemembrane

Water Saltsolution

REVERSE OSMOSIS (RO) THEORY

Reverse Osmosis If a pressure higher than the

osmotic pressure is applied onthe concentrated solution, the

flow will be reversed.

Only water from theconcentrated solution will be

pressed through the membrane.

Membrane Material

Cellulose Acetate

Polyamide, Polysulfone

Working Conditions

Pressure 10 – 60 bar

Temperature 5 – 25 ° C Semi-permeablemembrane

Water Saltsolution

Pressure

REVERSE OSMOSIS (RO) THEORY

TYPICAL 2-STAGE RO SCHEMATICS

Branch

Branch

2nd stage buffer tank


Second stage RO cartridge

First stage filtrate feeds second stage ROwith excess back to 1st stage buffer tank.

1 s t s t a g e

r e j e c t c o n c e n t r a t e

Air breakto sewer

Second stage reject water goes back to first stage buffer tank

Second stage RO watermeets Pharmacopoeia

standards Outlets or storage

1st stage buffer tank

Water from softener or de-ioniser

Water returns to 1st stage buffer tank

Hygienic pump

First stage RO cartridge

High pressurepump

AdvantagesLess chemical handling than ion exchange (IE)More effective microbial control than ion exchangeIntegrity test possibleRemoves most of organic and non-organic contaminantsLess energy consumption than distillation

Disadvantages

Water consumption higher than IE unless waste-water is re-usedDanger of microbial growth on membraneSterilization/sanitization with steam not possibleNo removal of dissolved gasesWorking at high temperature (>65 °C) only possible with certain typesof membrane

Many uses

Purified waterFeeding of distillation units or ultra-filtration unitsWater for Final RinseWater for Injections (if and where permissible)

USE OF REVERSE OSMOSIS

REVERSE OSMOSIS

ELECTRO-DEIONIZATION


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

Before being fed into the EDI module the permeate produced by the reverse osmosis system is dividedinto three sub-streams.

EDI feed water is passed through the diluate chambers filled with ion exchange resin. Through theaction of the electric field, the anions migrate through the resin bed in the direction of the anode. As aresult they pass through the anion-permeable membrane and arrive in the adjacent stream ofconcentrate.

The cations migrate through the resin bed in the direction of the cathode, pass through the cation-permeable membrane, and so likewise enter the stream of concentrate.With the concentrate stream, the ions areexpelled from the module.The electrolyte stream flushes out the gasesthat are created at the electrodes, along with the ions, and carry them cut of the module

As a result of the electrical voltage, watersplitting occurs in the resin bed of thediluate chamber.The H+ and OH- ions that are needed forthe regeneration of the exchange resinare created.These regenerate the resin bed onan ongoing basis.In this way continuous operation can bemaintained, without any need to switch oft thesystem for regeneration purposes.


• 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 80°C, and sterilization at 121°C

ULTRA-FILTRATION

FILTRATION

TYPICAL PW STORAGE AND DISTRIBUTION SCHEMATIC

Watermust be

keptcirculating

Spray ball

Optionalfilter 0,2 µm

Air breakto drain

Points ofuse

Hygienic pump

UV light

Feed Waterfrom

DI or RO

Heat Exchanger

Flowmeter

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

Hydrophobic, heated

air filter& burst disc

TYPICAL PW STORAGE AND DISTRIBUTION SCHEMATIC

Watermust be

keptcirculating

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

Optionalfilter 0,2 µm

Air breakto drain

Points ofuse

Hygienic pump

UV light

Feed Waterfrom

DI or RO

FlowmeterHydrophobic, heated

air filter& burst disc

Ozonegenerator

DISTRIBUTION LOOPS

TYPICAL PW GENERATION AND STORAGEINSTALLATION

PURIFIED WATER

is obtained from drinking water (inaccordance with the relevantnational standards)

contains no added substances

is obtained by a suitable process

requires frequent sanitization andmicrobiological monitoring toensure quality

HIGHLY PURIFIED WATER

USP and JP allow for WFI to beproduced by either distillation ormembrane processes (e.g. RO/EDI/UF)

Ph Eur allows only using distillation

”Highly Purified Water” meets thequality criteria for WFI but is producedthrough less expensive membraneprocesses

HPW intended for use in thepreparation of products where water ofhigh biological quality is needed, exceptwhere 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 orsuperior 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 OfUse heat exchangers, where necessary

PH.EUR.

USP SPECIFICATIONS: PW >< WFI

CFU=Colony Forming Units

PW* (Purified Water) WFI (Water forInjections)

Water conductivity andpH

< 2.1 µS/cmpH 5-7

< 2.1 µS/cmpH 5-7

Total Organic Carbon(TOC)

0.5 ppm 0.5 ppm

Aerobic Microbial

Contamination

< 100 CFU/ ml < 10 CFU/100 ml

Endotoxin content Not Specified < 0.25 EU/ml

Production

Methods

Obtained by suitableprocess

Obtained by suitableprocess and purified byDistillation or RO (or UF)

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 dissolvedsolids, which have been ionized in a polar solution such aswater.

The unit of measurement commonly used is one millionth of aSiemens per centimeter (micro-Siemens per centimeter orµS/cm)

Temperature plays a role in conductivity, and because ionicactivity increases with increasing temperature, conductivitymeasurements are referenced to 20°C or 25ºC (depend ing onthe pharmacopoeia)

TOTAL ORGANIC CARBON

Introduction of organic matter into water systems occurs not onlyfrom 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, andthus between TOC concentrations and the levels of endotoxinsand microbes.

Virtually all TOC analyzers measure the CO2 formed when organiccarbon is oxidized and/or when inorganic carbon is acidified.

Oxidation is performed either through Pt-catalyzed combustion, byheated persulfate, or with a UV/persulfate reactor.

Once the CO2 is formed, it is measured by a detector: either aconductivity cell (if the CO2 is aqueous) or a non-dispersiveinfrared cell (after purging the aqueous CO2 into the gaseousphase)

TOC is an important tool in cleaning validation.

Glassware cleaning is important, as TOC is a very sensitive test

WFI COMPLETE PROCESS

Feedwater

Reverseosmosis

Electro-deionisation Tank

Distillation system

WFI loop

Tank

Pointof Use

Pointof Use

Components used:• Heat Exchangers• Pumps• Valves• Installation material• Tank Equipment

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)

PRODUCTION OF WATER FOR INJECTIONS

DISTILLATION SYSTEMS

The pharmaceutical still chemically and microbiologically purifieswater by phase change and entrainment separation.In this process, water is evaporated producing steam.The steam disengages from the water leaving behind dissolvedsolids, non-volatiles, and high molecular weight impurities.However, low molecular weight impurities are carried with watermist / droplets, which are entrained in steam.A separator removes fine mist and entrained impurities, includingendotoxins.The purified steam is condensed into water for injection. Distillationsystems are available to provide a minimum of 3 log10 reduction incontaminants such as microorganisms and endotoxins.Three designs are available

- single effect (SE),

- multi-effect (ME)

- vapour compression (VC).

In a multi effect still, purified steam produced in each effect is used to heatwater 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 feedwateris compressed and subsequently condensed to form distillate

VC stills require water softening for removing calcium and magnesium asminimum.

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.

DISTILLATION SYSTEMS

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

Watermust be

keptcirculating

Spray ball

Air breakto drain

Pointsof Use

UV light

Feed Water from Distiller

Heat Exchanger

Hydrophobic air filter& burst disc

Hygienic pump

Flowmeter

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

GMP EXPECTATIONS

“Issues such as quality of installation, sampling and testingprocedures, operating and maintenance procedures, recordkeeping, etc. often have greater significance than the particulartechnologies selected to purify and distribute the water.”

Source: ISPE Baseline Guide

Continous Flow

- system not in service, re-circulation lineshould be included

Turbulent Flow / Velocity

- Reynolds number >4000

Frequent Sanitization

Sampling valves: between eachpurification step

operating temperature

Continuous Microbial control Methods:

- Elevated or reduced temperatures

- Ozonation of distribution systems

GMP CONSIDERATIONS FOR WATER SYSTEMS

• Proper Slope/ Drainability

fully drainable for systems that willnever be sanitized

allow for draining of equipment andassociated piping

• Finishes

Product contact, less than Ra 0.8 µm

• Deadlegs: 6-D Regulation as aminimum

• Cleaning / Passivation

• Critical Instrument Review:

-Calibration; Conductivity and

Temperature

-Temperature at coldest point by hot

water sanitization

Microbial Design Considerations for system and loop

3. The water is contaminated as itpasses through the valve

2. Bacteria can grow whenthe valve is closed

1. Ball valves are unacceptable

Stagnant water inside valve

VALVES

DIAPHRAGM VALVES

Principle design:

DIAPHRAGM

VALVE BODY

F

DIAPHRAGM VALVES

FUNCTION OF DIAPHRAGM VALVE

SHELL & TUBE HEAT EXCHANGER

Sanitary shell & tube heat exchanger where the productflow goes through several seamless, electropolishedtubes with the service media on the shell side.

In caseof leakage

DOUBLE TUBE EXCHANGERS

To prevent cross-contamination, two tube sheets areconnected at both ends with the tubes expanded intothe tube sheet.

POINT-OF-USE COOLER

A module installed as a point ofuse cooler

POINT OF USE INSTALLED IN SUBLOOP

Coolant

Point of Use

T

Hot Loop Hot Loop

Restriction Orifice

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

This subloop leads to addedpressure drop in the main loopwhich leads to the use of a largercirculation pump

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

PVC Polyvinyl ChloridePE PolyethyleneUHMW PE Ultra high molecular weight PECPVC Chlorinated Polyvinyl ChloridePP Polypropylene (Natural or Gray)PVDF Polyvinylidene FluorideHP PVDF High Purity PVDFTeflon -various forms – PTFE Polytetrafluoroethylene – ECTFE Ethylene chlorotrifluorethylene

(Halar) – ETFE Ethylene tetrafluoroethylene – CTFE Chlorotrifluorethylene – PFA Perfluoroalkoxy resinPEEK Poly Ethyl Ethyl Ketone316L SS stainless steel

PIPING MATERIALS

American Society for Testing and Materials

American Iron and Steel Institute

STEEL

STAINLESS STEEL MATERIALS

Material Designation

DIN AISI

1.4404 316LLow-Carbon-steel

1.4435 316L

1.4571 316Ti Titanium-stabilized

1.4401 316 V4A (old German Classification)

1.4539 904 Alternative material for rouging avoidance (?)

Today we see mainly low carbon steel in use for high puritywater systems,In previous times steel grades such as 1.4571 and 1.4401 hadbeen 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

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

GASKET MATERIAL

PIPES SIZES

Securing turbulent flow conditions

Pipeline sizing

DIN 11850

(external diameter) mm

x (wall thickness) mm

Minimum pass

At 20 °C At 85 °C

m/s m³/h m/s m³/h

DN 10 13 x 1,5 2,5 0,7 0,9 0,2

DN 15 19 x 1,5 1,6 1,1 0,5 0,4

DN 25 29 x 1,5 1,0 1,9 0,3 0,6

DN 40 41 x 1,5 0,7 2,7 0,2 0,9

DN 50 53 x 1,5 0,5 3,6 0,2 1,2

SURFACE QUALITY

Besides the materials of construction the quality of media contact surfaces isone 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 µm without problems. Well polished stainless steel

surfaces and specially treated tubes can get down to Ra ≤ 0,4 µm

Another enhancement can be reached by electropolishing of surfaces. This

allows to get down to a surface roughness of Ra ≤ 0,2 µm.

There is no significant improvement of microbiological water quality known

using materials with a surface roughness Ra ≤ 0,8

Ra-VALUE

Mean

Avg. dev.

Ra

Material surfaces Attached bacteria

Avg. dev.

Ra

Identical Ra-value not necessarily identical cleanability !!!

– The average surface height deviation from the mean, measured with a profilometer

– Result is a length measurement

PASSIVATION

Passivation is the removal of exogenous iron or ironcompounds from the surface of stainless steel by means of achemical dissolution, most typically by a treatment with an acidsolution that will remove the surface contamination, but will notsignificantly affect the stainless steel itself, for the purpose ofenhancing the spontaneous formation of a thin (1 µm)protective, transparent passive film (chromium oxide).

The passivation process removes "free iron" contamination leftbehind on the surface of the stainless steel from machining andfabricating.

These contaminants are potential corrosion sites that result inpremature corrosion and ultimately result in deterioration of thecomponent if not removed

ELECTROPOLISHING

Enhanced Surface Finish

Corrosion Resistance(Passivated Surface)

Removes Polishing Compounds

High Lustre Appearance

An electropolished surface will besmoother than a mechanicallypolished surface with the same Ra

Electropolishing removes free ironfrom the surface, increasing theCr/Fe ratio at the surface, thusenhancing the passive layer

Electropolishing reveals surfacedefects for simple visual inspection.

ORBITAL WELDING

ORBITAL TUNGSTEN INERT GAS WELDING

Principle

• During the weld the material remainsstationary while the tungstene (wolfram)automatically travels around the tube

• The power supply controls the weldingcurrent, pulsation rate and travel speed

• Possible to change the welding parametersduring the welding

• Possible to print real welding parameters

• 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.

ORBITAL TUNGSTEN INERT GAS WELDING

WELDING DOCUMENTATION

2

3

4 5

1

1 7

1 6

1 5

1 4

6

7

1 3

1 2

1 1

8 9

1 0

Marking of each single weld in order to maintain traceability to

welding documentation

Essential for qualification

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 withordinary steel

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

DISINFECTION WATER SYSTEMS

CHEMICAL SANITIZATION

Efficient and accepted method

Low Investment (Dosing unit for chemicals)

Automatic sequence (only for verification of chemical substance )

Dosingpump

Dosingpump

EDI

SEPTRON ® EDI

Concentration Tank

Heater Exchanger

Reverse Osmosis

filter

90 µmSoftener

Safe filter

5 µmPump

Raw-

water

Circulation -

Piping

M

M

PurifiedWatertank

HOT WATER SANITIZATION

In-line HE (electrical or

Steam) brings systemwater to > 80°°°° C

Re-circulation incl.

piping from and tostorage tank

Automatic sequence EDI

SEPTRON ®

EDI

Concentration Tank

Heater Exchanger

Reverse Osmosis

filter

90 µmSofteners

Safe filter

5 µmPump

Raw-

water

Circulation

piping

M

M

PurifiedWatertank

Efficient and acceptedmethod

No chemicals handling orstorage

Easy documentation(Recorder print-out)

Rapid operational startafter sanitization

No chemical substancesto rinse out, no polluteddrain/waste water

0

10

20

30

40

50

60

70

80

90

100

0:00 0:30 1:00 1:30 2:00 2:30 3:00 3:30 4:00 4:30

Time [h]

°°°°C

Start heat-up

Start

System ready

Sanitizing

Temperature Profile

HOT WATER SANITIZATION

Ozone is very reactive but also unstable.It cannot therefore be stored and has to be produced where and when it isneeded.Ozone is produced from oxygen-containing gases in ozone generators bymeans 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 twodischarge chambers, through which gas flows.Some of the oxygen molecules in the input gas break down in the electricfield and immediately attach themselves to free oxygen molecules, formingozone

OZONISATION

OZONE EFFICIENCY

Hoffmann-La Roche (Swiss Pharma 1983)

Sanitizing generally at 25ppb

OZONE OR HOT WATER SANITIZATION

0

10

20

30

40

50

60

70

80

90

100

110

120

130

1

Operation time

G e r m

c o u n t [ c f u / m l ]

Action level

purified water

Action level

water for injection

Continuous sanitisation

by ozone

< 10 cfu/ml

Microbiological behaviour in ambient purified water loops with ozone ( ~25 ppb)

0

10

20

30

40

50

60

70

80

90

100

110

120

130

1

Operation time

G e r m c

o u n t [ c f u / m l ]

Action level

purified water

Microbiological behaviour in ambient purified water loops with

periodic hot water sanitisation

Periodic sanitisation by

hot water (>80°C)

Accepted contamination

Ozone - continuously Hot Water- periodic

SANITISATION OF COLD DISTRIBUTION SYSTEMS:OZONE OR HOT WATER ?

Criterion Ozonization (10 – 100 ppm) Hot Water Sanitisation

Microbiological

safety

Very high

- Reduction of CFU

- Reduction (removal) of TOC

- Reduction of endotoxins

High

- Reduction of CFU

Efficacy Very high

Because of continuous circulation, even during water

consumption

High

But only if no consumption of water is planned

Installation

costs

High

Ozone generator, static mixer, UV-generator (to destroy ozone

before entering the distribution loop), ozone monitor, (ozone

monitor for the environment)

Relatively low

Heat exchanger and insulation

Running costs Low

Electricity for ozone and UV generator

High

For periodic heating and cooling

Maintenance High

- Exchange of UV-Radiator every 10.000 h

- Calibration of sensors every year

- Change of electrolyte every two years

Low

- Change of gaskets (periodically)

Process

Continuity

Very high

No interruption necessary during production or consumption

Conditional

Interruption necessary for sanitisation

Material

Stress

Low

Selection of suitable gasket materials (elastomers) required

Medium

Eventually roughing

Space

requirement

Low 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 dangerousmicroorganisms to multiply, rendering them harmless tohumans and the environment.

It falls to the left of visible light with higher energy levels andwavelengths between 100 and 400 nm.

One of the most effective wavelengths and the one most oftenused for disinfection is at 254 nm. A watertight quarz tubesurrounds each lamp.

The liquid to be disinfected is passed through the quartztubing.

The gas plasma generated in the lamp emits light with aprimary wave length of 253.7 nm.

This intensive UV light reaches the microorganisms in thewater and impacts directly on their DNA.

UV DISINFECTION

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. Designed

2. Constructed

3. Maintained

4. Operated within design limits

5. Controlled to prevent microbial growth

WATER TREATMENT GUIDANCE

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 microbiologicalspecifications

• Sampling instructions

• Test procedures

• Responsible persons

• Training requirements

WATER QUALITY MANUAL

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 Kick-off meeting

2 Design

3 Design Approval (DQ)

4 Purchasing

5 Receiving Inspections

6 Manufacturing

7 Welding Inspection

8 Software Review (office tests)

9 Commissioning & Start-up 1 (skid-mounted equipment)

10 Internal pre-FAT

11 Factory Acceptance Tests

12 Shipments

13 Installations on site (electrical / mechanical)

14 Commissioning & Start-up 2 (complete systems)

15 Site Acceptance Tests

16 IQ / OQ

17 Training

18 Hand Over

V-MODEL

INSTALLATION QUALIFICATION

1. Documentation :Drawings, P&IDs, isometryCertificates calibration« Technical Datasheet » and drawings componentsMaterials certificates (Mill tests)Operation and maintenance manuals, list of spare partsPassivation reportWelding reports, qualification welders, weldingsamples, analytical report inert gasEndoscopies and X-Ray reportsSOPsFilters certificatesSoftware (version)2 Verification of critical components:ValvesFilters : cartridges and housingsConnections tri-ClampComponents of installation: softener, carbon filter,chemicals tanks and pumps, UV, RO, intermediatetanks, distribution system, etc.

2A) Verification of non critical components :From water entrance until RO3. InstrumentationA) Critical :Conductivity (loop and tank)FlowmetersTOCTemperaturePressure in loopB) Non critical :HardnessLevel controlLocal pressures4. Specific testsPre-treatment :Leaks, correctness of installationLOOP:RoughnessSlopes, angles valvesDead legsPassivationCleaningIdentification elementsVerification of connections:Electricity, compressed air, feedwater

OPERATION QUALIFICATION

Calibration (control instruments and instruments used intestsEmergency stopTest for electrical breakdownSOPs (approved)TrainingOperating sequencesOperation pump(s)Alarms: simulated and non simulated (set-points)I/O (input – output)Interlocks

Tests for water quality:Pre-treatment and feed-waterTest pre-treatment outlet and RO outlet

PERFORMANCE QUALIFICATION (PQ)TOC

Conductivity, chemical testsBioburden (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 2–4 weeks should be spent carrying out further intensive monitoring while deploying all the refined SOPsafter 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. Theapproach 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 accordancewith 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 thisphase 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 proceduresproven 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 microbiologicalattributes. Offline samples should be taken from points of use and specific sample points. Samples from points of useshould 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 accordancewith the related marketing authorization), and should include, as appropriate, determination of conductivity, pH, heavymetals, 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 intoaccount 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

Post-treatment

Point of ReturnThe quality of water the piping

system distributes Point of DistributionThe quality of water thesystem design produces

Points of UseThe quality of water procured

from the user point configurations

and sample points

Pump

CLEAN STEAM

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

Water Steam

VaporisationVaporisation

CondensationCondensation

STEAM STERILISATION

STEAM STERILISATION

Steam sterilization is considered the elective methodby all Pharmacopeias, Standards and Guidelines.

Accordingly, it must be preferred, unless problemsof incompatibility of the material to be sterilizedwith the temperature, humidity or pressureof the steam make it indispensable to useanother method.

EMEA Decision tree

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, avolume 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 + humiditythat produces the sterilizing effect of steam.

Contact can be:

Direct (e.g. a surgical instrument, sterilized loose or packaged in a steam-permeable 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 thesame 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-onecorrespondence 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 and3.04 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 ananhydrous oily solution, no sterilization occurs, or rather only the outer surfaces of the box and of theampoule 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 noteliminated completely, it stratifies in the lower parts of the chamber and of any empty open containerswhose mouth faces upward.This prevents the correct sterilization conditions from being achieved.

STEAM STERILISATION

ClosedClosed

OpenOpen

SteamSteam

SteamSteam

ClosedClosed

OpenOpen

SteamSteam

SteamSteam

OpenOpen

SteamSteam

SteamSteam

ClosedClosed

OpenOpen

AirAir AirAir

ClosedClosed

OpenOpen

AirAir AirAirGravity

Vacuum

STEAM STERILISATION CYCLES

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

Steam generated may carry droplets of the feed water which might contain ions, other dissolvedmaterials and particles, volatile compounds, pyrogenic material (endotoxins) and so on, that maycontaminate the sterilized goods.

In practice the terminologies plant (process) steam, filtered steam, clean steam and pure steam areoften 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 theboiler or distribution piping system are often present and could contaminate the goods. Somecontaminants 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 µm stainless steel filter to removeparticles. Colloidal iron from the piping system is difficult to remove and will aggregate after filtering, toshow up as particulate iron oxides. At high steam velocities condensate and unevaporated feed waterwill 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 anyseparation 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 arisk of such contaminants being carried over in droplets, together with the steam generated. Tominimize this contamination the steam can be filtered through a 3-15 µm 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 detectionsystem employed.

Pure Steam

Condensate of Pure Steam is expected to meet the requirements for WFI. This means it should have alow ion content, an endotoxin level below 0,25 IU/ml and a low level of particles. The steam shouldbe 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 canbe 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 sterilemedicinal product is sterilized

STEAM QUALITIES

Pure Steam Monograph (USP 29)

Pure Steam is water that has been heated above 100 degrees Celsius andvaporized in a manner that prevents source water entrainment.

It is prepared from water complying with the U.S. EPA NDWWR, or withdrinking water regulations of the EU, Japan or with WHO drinking waterguidelines.

It contains no added substance .

The level of steam saturation or dryness, and the amount of non-condensablegases are to be determined by the Pure Steam application.

[Note: Pure Steam is intended for use where the steam or its condensatecomes in contact with the article or the preparation. Pure Steam quality isdifficult to asses in its vapour form; therefore its condensate is used to test itsquality. The process used to collect the condensate for analysis must notadversely 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.

PURE STEAM

Physical properties of clean steam, such as dryness, superheat, noncondensable

gases and steam/air homogeneity, will influence the bacterial reduction properties. Steam for sterilizationpurposes 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, maycause a temperature lag in areas where the excess has settled. After sterilization it would also be difficult todry the goods.

Superheated steam will remove the moisture from the bacteria present. If micro-organisms are not properlyhydrated they become more resistant to heat and require longer sterilization times.

PHYSICAL PROPERTIES OF CLEAN STEAM

PRODUCTION CLEAN STEAM

STEAM STERILISATION

unistra 03 water 2012 mode de compatibilite

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