Workshop May 20th 2013

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WORKSHOP May 20th 2013 ACQUA PER USO FARMACEUTICO

Speaker Pasquale Della Valle
ELETTRACQUA Technical and Sales Manager
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WORKSHOP May 20th 2013 WATER FOR PHARMACEUTICAL PURPOSES
AGENDA
1. Introduzione 2. Opzioni di Pretrattamento 3. Opzioni di Trattamento Finale 4. Stoccaggio e Distribuzione 5. Validazione 6. Comparison Compendial Water ANVISA vs USP35 and EP7th Ed.
INTRODUCTION
1. INTRODUZIONE
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INTRODUZIONE
La selezione della qualit necessaria per l'acqua o vapore puro
potenzialmente la fase pi critica

nella pianificazione di un nuovo progetto di produzione di acqua per uso farmaceutico o sistema di vapore puro, da un punto di vista normativo, tecnico e finanziario.
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INTRODUZIONE
Luso dellAcqua nel settore farmaceutico include le seguenti applicazioni : - Come ingrediente nella formulazione di specialit farmaceutiche - Come ingrediente nella produzione di principi attivi (API) - Come risciacquo finale durante Clean in Place (CIP) delle apparecchiature di produzione - Come solvente o diluente per i processi di ricerca o di laboratorio
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INTRODUZIONE
Il design,costruzione,commissioning e validazione del sistema acqua per lindustria farmaceutica rappresenta una importante sfida poich deve essere conforme alle prescrizioni delle cCMP,oltre che rispettare tutte le leggi e le regolatorie locali.
WATER OPTIONS:I requisiti qualitativi delle acque impiegate nelle produzioni farmaceutiche sono guidate dalle caratteristiche del prodotto.Le monografie ufficiali(USP e EU) definiscono I requisiti minimi per ciascun tipo dacqua.In ogni caso la scelta finale della qualit dellacqua in relazione allimpiego al quale destinata,resta di specifica responsabilitt della Azienda Farmaceutica . Le acque di uso farmaceutico sono divise in due categorie: Compendial water e Non compendial water
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INTRODUZIONE
Le pharmacopee pi importanti: United States Pharmacopoeia (USP), European Pharmacopoeia (EP) Japanese Pharmacopoeia (JP) Definisco due Compendial Water and Steam
Purified Water (PW) Water far Injection (WFI) Pure Steam (PS) Highly Purified Water(HPW),EU only
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INTRODUZIONE
PHARMACEUTICAL WATER QUALITY DECISION TREE
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INTRODUZIONE
Il controllo di tutti i parametri critici di processo sono necessari, quando possono avere diretta conseguenza sul prodotto finale. I requisiti minimi per i metodi di produzione, la qualit dell'acqua di alimentazione, e gli attributi di qualit per le acque compendial sono definite nelle specifiche monografiche.
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INTRODUZIONE
La figura mostra la GUIDE LINE utile nel processo decisionale, nella definizione iniziale della tipologia di acqua necessaria e quindi determinare il progetto del sistema necessario dal pretrattamento al trattamento finale.
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INTRODUCTION
2. PRETREATMENT OPTION
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PRETREATMENT OPTION
Pretrattamento viene definito linsieme di tutte le fasi di trattamento necessarie a garantire che la qualit dell'acqua di alimentazione diventi di qualit adeguata ad ottimizzare le prestazioni del trattamento finale.Esse sono definiti nei seguenti step.
Control of fouling :rimozione della torbidit e colloidi

Control of scaling :rimozione o controllo della durezza e metalli
Control of Organics:riduzione delle sostanze organiche e batteriche
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PRETREATMENT OPTION
Control of fouling :rimozione della torbidit e particolati TORBIDITA

causata da materiale in sospensione e colloidale, che pu essere di natura organica o inorganica ed altri microorganismi .
PARTICOLATI
Tipicamente sono minerali insolubili. In particolare silice coloidale.
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PRETREATMENT OPTION
La rimozione della torbidita e particolato fondamentale per evitare lo sporcamento dello step finale del trattamento, in particolare lintasamento delle membrane di Osmosi Inversa
I metodi pi utilizzati per rimuovere TORBIDITA E PARTICOLATO,sono: Filtrazione multimedia Ultrafiltrazione
la
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PRETREATMENT OPTION
FILTRATION SPECTRUM
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PRETREATMENT OPTION
Filtrazione Dualmedia :sono formati da contenitori in pressione,con allinterno materiale filtrante formato da quarzite e carbone antracite.
Advantage:
Large capacity per unit cost Low cost of operation
Disadvantage:
Particle reduction limited to 10m (approx)
Can become a source of microbiological contamination if improperly maintained, designed or operated
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PRETREATMENT OPTION
Ultrafiltration
Vantaggi :
La Ultrafiltrazione una barriera invalicabile per tutti microorgnismi (virus e batteri) e tutti quei composti che formanno la torbiditt oltre che per la totalitt dei colloidi. Lefficacia del processo della filtrazione indipendente della caratteristica dellacqua di alimentazione. UF pore rating : 1000-100,000 Daltons cut-off. UF membrane sono in polysulfone in configurazione fibra cava(hollow fiber). UF membrane hanno pori di filtrazione in un range 0,01-0,1 microns.
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PRETREATMENT OPTION
VANTAGGI DELLA ULTRAFILTRAZIONE Rispetto ai processi di trattamento convenzionale: Alcune particelle colloidali hanno una dimensione inferiore 0,2 micron (per essempio silice colloidale) Quindi non sono trattenute dal dual media filter che limitato a circa 10m, ne dalla filtrazione a cartuccia. E hanno un impatto drammatico sulla membrana di RO causando un rapido sporcamento e il fuori servizio. Fasi di trattamento successive avranno maggiore efficienza e affidabilit dovuta al fatto che tutta la torbidita ed i colloidi saranno stati completamente eliminati. .
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PRETREATMENT OPTION
CASE STUDY: Laboratrio Teuto Brasileiro

PROBLEMATICHE RILEVATE SULL IMPIANTO PRE ESISTENTE,FORNITO DA ALTRO SUPPLIER DA 7/8 ANNI
PROBLEMATICHE DELLACQUA DI ALIMENTAZIONE TORBIDITA: 0.22-11.1 NTU INDICE DEI COLLOIDI: SDI O,3-8 IL PARTICOLATO COLLOIDALE PASSA SIA IL DUALMEDIA FILTER E IL FILTRO A CARTUCCIA
IMPATTANDO DRAMMATICAMENTE SULLE MEMBRANE DI OSMOSI INVERSA CAUSANDO LA
Sostituizione delle membrane circa 6 mesi con notevole costo di essercicio e fuori servizio di produzione
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PRETREATMENT OPTION
DRAMATICALLY IMPACT on the RO Performance reduction of capacity of PW production high frequency of cleaning reduction of RO membrane life: replacement every 6/8 months ELETTRACQUA HA FORNITO NEL 2011 UN NUOVO IMPIANTO DI PRODUZIONE WFI,REALIZZATO CON MEMBRANE DI RO.IL SISTEMA DI PRETRATTAMENTO E STATO PROGETTATO CON UF LACQUA PRETRATTATA INVIATA AL PRIMO PASSO DI RO HA I SEGUENTI PARAMETRI CHIMICO FISICI: Turbidity: less 0.1 NTU SDI: less 0.1 UN ANNO DI FUNZIONAMENTO SENZA NESSUN CLEANING CHIMICO DELLE MEMBRANE.VIENE CONFERMATO IL LIFE TIME DELLE MEMBRANE DI RO NON INFERIORE A 5 ANNI.
IN SEGUITO A QUESTI RISULTATI TEUTO HA COMMISSIONATO LA INSTALLAZIONE DI UN NUOVO SISTEMA DI UF A MONTE DEL VECCHIO IMPIANTO DI PW
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PRETREATMENT OPTION In both the plant Elettracqua has supply DOW UF modules that utilize a double-walled hollow fiber H-PVDF membrane with a very small pore diameter (0,03 nominal pore) for excellent removal of particulate matter and bacteria, and most viruses and colloids.
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PRETREATMENT OPTION
IN IN
BACTERIA
FILTRATE
VIRUS
PROCESS OPERATIONS
Filtration Step Outside-In flow configuration for high tolerance to feed solids UF is operated at a constant permeate flow. The transmembrane pressure (TMP) will naturally increase over time, and the module can be cleaned by back-washing and air-scouring to remove the fouling layer for longer service life.
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PRETREATMENT OPTION
Backwash (BW) Step Clean In Place Cleaning (CIP) Step
Cleaning Step The frequency of the cleaning step dependent on the feed water quality
Chemically Enhanced Backwash (CEB) step
Air Scour Step
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PRETREATMENT OPTION
Control of scaling :controllo della durezza

Il controllo della durezza(Ca+Mg) necessario per evitare la precipitazione di composti incrostanti,come carbonati sulle membrane di Osmosi Inversa.
I sistemi di controllo includono METHODS of CONTROL include :
- Addolcimento con resine a scambio ionico - Dosaggio di prodotti antiprecipitanti(antiscalant)
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PRETREATMENT OPTION
Softening by Ion Exchange

Ion exchange resins reduce the hardness by replacing magnesium and calcium with sodium
Ca2+, Mg2+, Na+, K+ HCO3-, Cl-, NO3-, SO42-, SiO2
NaCl 10 %
SAC
Na+, HCO3-, Cl-, NO3-, K+ , SO42-, SiO2
Regenerant Waste
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PRETREATMENT OPTION
Softening by Ion Exchange

Softening by Ion Exchange is a very popular pretreatment step, but in case of low hardness content it is easy to control the hardness by Antiscalant Dosing before the 1st Pass RO
The typical Brazilian Raw Water analysis shows: low hardness: less 50ppm as CaCO3 low TDS high Turbidity (TSS, heavy metal and colloids, specially colloid silica)
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PRETREATMENT OPTION
Antiscalant Dosing
LAntiscalant sono dei composti chimici organofosfonati, a elevatissimo peso molecolare
APPROVATI by FDA-EPA-EP-WHO
Lantiscalant, dosato in piccola quantitt in acqua di alimentazione (3-5 mg/L) vanno chimicamente a legarsi al calcio, magnesio, ferro e silice in forma ionica - elevando il loro prodotto di solubilitt,quindi questi composti chimici,restano perfettamente in soluzione nellacqua e vengono totalmente rigettati delle membrane di Osmosi Inversa senza che vengono contaminate
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PRETREATMENT OPTION
SANITIZAZIONE
I necessarie metodi di santizazione per evitare eccessiva crescitt microbica sono : Sanitizazione chimica,oppure termica Controllo di Temperatura,a valori inferiori a 18C
Periodic Hot Water Sanitization Temperatures above 80C result the complete killing of all nonresistant bacteria.
> 80C
15C
Operating Temperatures below 15C avoid the bacterial growth
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PRETREATMENT OPTION
DEBATERIZAZIONE RAGGI ULTRAVIOLETTI (UV)
The UV light, 254 nm wavelength, deactivates DNA in the microorganisms, preventing duplication and leading to a reduction in bacteria. The feed water to a UV system needs to be free of suspended solids, which can "shadow" bacteria, preventing adequate UV contact. UV lights can not be used as sole means of microbial or organic contaminant control, but must be as a part of a total microbial control plan.
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PRETREATMENT OPTION
IPOCLORITO DI SODIO
Municipalities frequently use chlorine, often introduced as sodium hypochlorite to disinfect water before and during distribution.
Chlorine is fed into the system to kill bacteria at typical dosage levels of 0.2 ppm to 2.0 ppm.
Chlorine concentration should be monitored in the feed water and in parts of the pretreatment system prior to its removal.
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PRETREATMENT OPTION
IPOCLORITO DI SODIO Deve essere totalmente eliminato prima di alimentare le membrane di Osmosi Inversa, che essendo di materiale Poliamide vereberro iremediabilmente ossidate.
PRINCIPALI SISTEMI DI RIMOZIONE IPOCLORITO DI SODIO:
Activated Carbon Reduction with Sodium Bisulfate dosing
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INTRODUCTION
3. FINAL TRATMENT OPTIONS
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FINAL TREATMENT OPTIONS - NON-COMPENDIAL WATER and COMPENDIAL PURIFIED WATER
PW, HPW and Non-compendial water can be produce by an extensive combination of unit processes in various combination as
membrane degasification (CO2 removal) Ultrafiltration microfiltration ultraviolet light Reverse Osmosis Electrodeionization
The most common PW system design implement a Single Reverse Osmosis Pass with
another Reverse Osmosis Pass RO + RO
or
a continuous electrodeionization stage RO + EDI
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REVERSE OSMOSIS
Utilizing semi-permeable membrane, means that the membrane is permeable for water while impermeable for salts, acids, bases, colloids, bacteria and endotoxins. For Pharmaceutical water production, RO membrane have a spiral wound configuration and are available in cellulose acetate or thin film composite (polyamide). The majority of pharmaceutical systems utilize thin film composite membranes. The optimum membrane selection is based upon an analysis of capital cost, operating cost, membrane life, rejection and bacteria control.
PERMEATE FLOW CONCENTRATE
PERMEATE
CONCENTRATE
Advantages highest rejection of contaminants operate effectively at lower temperatures (4C and higher) operate effectively at low pressure (7 bar g and higher) longer life expectancy Disadvantages higher initial capital cost low tolerance for chlorinated feed water
FEED WATER
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REVERSE OSMOSIS LIMITATIONS
RO cannot remove 100% of contaminants from water and has either very low or no capacity for the removal of several extremely low molecular weight dissolved organics. A concentrate flow is essential to remove the contaminants that are rejected by the membrane. The waste stream from an RO unit may be used for cooling tower make-up water or compressor cooling water, etc.
Recovery is defined as the percentage of feed water that becomes purified product water. Recovery can range from 20% (or less) up to 90%, depending on factors such as: feed water quality provided to the RO unit system capacity/configuration life cycle costs requirements A recovery unit with a high percentage output may have less waste to achieve the desired output rate, but will tend to have higher maintenance costs due to the fouling/scaling effects of the concentrate.
Produced water quality is dependent but not limited to membrane type, operating pressure, feed water quality.
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Carbon dioxide pass directly through an RO membrane and will be in the RO product stream at the same level as that in the feed water stream. Carbon dioxide in the RO product stream may increase the product conductivity beyond the PW Stage 1 conductivity limit. To reduce these potential issues, a degasification unit operation could be added before or after the RO process.
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HYDROPHOBIC HOLLOW FIBER MEMBRANE

The purpose is to remove the carbon dioxide (CO2)
Water on one side and strip gas on the other. The strip gas can be drawn by vacuum or pressurized on the inlet.
The strip gas lowers the partial pressure of the gas phase which causes the gases from the liquid phase to diffuse through the membrane into the gas phase.
Liquid Inlet
Advantages simple design and maintenance chemical free method simple installation low operation costs
Disadvantages more expensive than sodium hydroxide dosing
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SODIUM HYDROXIDE DOSING SYSTEM

In case of feed water CO2 value lower than 10ppm Raising the pH value to 8.3, is possible to convert the Carbon Dioxide to Bicarbonate, which is more readily rejected by the RO membrane.
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RO PRETREATMENT REQUIREMENTS
SCALING MINIMIZATION Scaling is possible since the feed water contaminants are being concentrated into waste water. Scale control is normally prevent by Using of water softening upstream of the membranes Injection of acids to lower the pH of feed water stream Dosing an antiscalant compound to prevent precipitation of dissolved ions
FOULING MINIMIZATION RO membrane fouling is reduced through the use of back-washable filters (multi-media, cartridge and ultrafiltration) and various microbial control pretreatment methods to reduce biological fouling OXIDATION MINIMIZATION The main causes of membrane degradation are oxidation of certain membrane materials and heat degradation. Thin film composite membrane system incorporate various compound for dechlorination, while protection against high temperature is normally incorporated where membrane material cannot tolerate high temperature.
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RO PERFORMANCE
Single pass RO typically reduce the contaminants more than 99%, but produced water dont meet the conductivity requirements of most compendial PWs Double pass RO can produce water than can pass the Stage 1 conductivity requirements. Membrane selection should be based upon: Pre-treatment requirements Operating performance characteristics Sanitization options Warranties Capital and operating costs Feed water source
RO unit should incorporate sufficient membrane area for reliable operation. On of the most important factors to optimize this are is fouling and scaling potential understanding. The Silt Density Index (SDI) reading gives an indication of the tendency of feed water to foul the membranes. Lower SDI means low membrane cleaning frequency. SDI optimal value is 3 RO system typically are designed at a specific operating temperature and pressure; any deviations from the baseline condition could changes the amount or the quality of produced water.
Ex. An increase in temperature above the design temperature could lead to increase permeate flow, but potentially decrease product water quality due increasing salts passage in the permeate.
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CONTROL AND INSTRUMENTATION

Proper instrumentation for monitoring and controlling critical and non-critical parameters of operation is essential to any RO system design. The product water quality from RO system is directly related to the feed water quality.
The most important parameters to control and measure are
FEED WATER
TEMPERATURE PRESSURE
PRODUCED WATER
CONDUCTIVITY TEMPERATURE PRESSURE FLOW RATE
WASTE WATER
FLOW RATE PRESSURE
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REVERSE OSMOSIS CONCENTRATE REUSE

Pretreated Water 4,2 m3/h BREAK TANK FIRST PASS RO = 75% 3,5 m3/h SECOND PASS RO = 85% 0,5 m3/h
TOTAL RECOVERY = 71,4%
4,7
m3/h
3 m3/h
1,2 m3/h 0,5 m3/h
RO DOUBLE PASS SYSTEM WITHOUT CONCENTRATE RECOVERY SYSTEM (CRS)
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Pretreated Water 3,42 m3/h BREAK TANK FIRST PASS RO = 75% 3,5 m3/h SECOND PASS RO = 85%
1,28 m3/h
TOTAL RECOVERY = 87,7%
4,7
m3/h
3 m3/h
1,2 m3/h
0,5 m3/h
CONCENTRATE RECOVERY SYSTEM
= 65% 0,42 m3/h
0,78 m3/h
1,28 m3/h
RO DOUBLE PASS SYSTEM WITH CONCENTRATE RECOVERY SYSTEM (CRS)
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Differential pressure exceeding 2,5 bar Salt passage increasing Product flow rate decreasing
RO MEMBRANE CLEANING IS NEEDED

CHEMICAL CLEANING Carry out by chemical cleaners Acid based cleaners to remove metals and salts Alkaline cleaners to remove silt and organic foulants Dedicated tank and pump are needed THERMAL CLEANING Carry out by Hot Water at 85C Specially constructed membranes are needed
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FINAL TREATMENT OPTIONS - NON-COMPENDIAL WATER and COMPENDIAL PURIFIED WATER ION EXCHANGE RESINS ION SELECTIVE MEMBRANE
+ +
ELECTRICAL FIELD
to continuously remove ionized species and regenerate the resins
=
CONTINUOUS ELECTRODEIONIZATION CEDI
Continuous, not in batch or intermittent Ionic transport properties of the ion exchange are primary sizing parameter
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Ionized species are drawn from the water passing alone the ion depleting cells and transferred into concentrate water stream passing across the ion exchange membranes that are permeable to ionized species and not to water. Power supply create a Direct Current electric field between cathode and anode that contributes to the ionic transport far.
Concentrate Concentrate Concentrate Concentrate
PURIFIED WATER
PURIFIED WATER
Purifying Compartment
Concentrate compartment
High voltage cause water splitting into H+ and OH- that regenerate continuously the cationic and anionic exchange. This continuous high regeneration level, allows the consistent production of high purified water. CEDI is commonly used after RO unit in order to produce water with low conductivity and organic levels, RO+CEDI system may produce water with conductivity 0,1 S/cm or lower. CEDI unit performance is a function of feed water quality.
ANODE
PURIFIED WATER
CATODE
FEEDING WATER
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ULTRAVIOLET LIGHT TREATMENT

for Polishing and Removal of specific contaminants
UV light treatment aims to decrease the bacteria growth inside the treated water
UV wavelengths and intensity level required depend on the expected function
Advantages Simple design and maintenance No waste stream Heat, ozone and chemical sanitization are possible Disadvantages Can be used only as part of a total microbial control plan No ion or endotoxin removal No disinfection residual Particulate can shield organism from UV light Dead organism are not removed from the water
254 nm units are used for limiting bacteria contamination, breaking the microorganism outer membrane to modify the DNA in order to avoid the replication
185 nm units are used for TOC (Total Organic Carbon) reduction
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FINAL TREATMENT OPTIONS
WATER FOR INJECTION WFI
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WATER FOR INJECTION (WFI)
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Distillation normally is used as the final processing step for quality WFI system To select appropriate technologies, the manufacturer of products should first consider where the products will be distributed and what regulations are applicable to those market Distillation technologies require adequate pre-treatment to prevent/minimize corrosion and scale formation and allow final unit operations to meet compendial requirements WFI should be produced using different technologies as Multiple Effect Water Still (ME) or Vapor Compression Still (VC), but normally the production steps are Water is evaporated, producing steam By means separation devices, steam will be disengage from water droplets that contain dissolved solids, non-volatiles and other impurities Pure Steam is condensed into WFI
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BASIS FOR ECONOMIC COMPARISON

The three primary factors affecting the operating costs of any still design are
INDUSTRIAL STEAM
COOLANT CONSUMPTION
ELECTRICITY
Using these estimates and the local cost of each utility, expense can be projected based on anticipation volume. The appropriate selection should be based on a comparison of operating cost versus capital cost
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CONTRUCTION MATERIALS and SURFACE FINISHING

The recommended material for the equipment is Stainless Steel AISI 316L, finishing Ra 0,6 m, polished and passivated, while for gasket materials should be suitable for the maximum temperature to which they will be exposed, normally silicone or PTFE FDA approved gasket are used
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CONDENSATE DISCHARGE

PURE STEAM
PURE STEAM CONDENSE
COOLING WATER
WFI PURE STEAM
OFF-SPEC WFI
INDUSTRIA L STEAM
FEEDING PURIFIED WATER
CONDENSATE
CONDENSATE LIQUID DISCHARGE
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FEED WATER PRE-HEATER and FINAL CONDENSER

In order to reduce the energy consumption and operation costs, two DTS Heat Exchanger are installed before the first distillation column. The exchanger recover and transfer the heat from produced Pure Steam and WFI to feed water
1st condenser Cool side : Feed Water Heat side : Pure Steam 2nd condenser Cool side : Cooling Water Heat side : Pure Steam
Pre-Heater Cool side : Feed Water Heat side : Condensate Discharge
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FIRST DISTILLATION COLUMN
Double Tube Sheet (DTS) design to safety the separation between aseptic product and industrial steam High steam velocity design
Efficient heat transfer design

Automatic control of feed water flow rate by means dedicated 4-20 mA level transmitter Automatic control and regulation of produced WFI according to WFI Storage Tank inside level Less thermal variations More continuatives operation
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SECOND and OTHER DISTILLATION COLUMN

Each column use as heating steam the pure steam coming from the previous column High steam velocity design Efficient heat transfer design Single tube design, because heating steam is pure steam Automatic control of feed water flow rate by means dedicated 4-20 mA level transmitter Every added column increase capital cost but reduce required industrial steam and cooling water amount (operating costs)
Plant steam pressure 8 bar 175C Capacit y lt/h 4 Steam Consumption kg/h Effects number 5 6 7
2.300
783
630
528
456
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CYCLONE SEPARATION SYSTEM

The heart of WFI production system is the separation of water droplets containing contaminants from the pure steam, by means a cyclone system installed inside each evaporation column. Two basic principle are used for this process: High Steam speed creating centrifugal forces that separate any entrained water particles and throw them to the outer wall of separator to drain. Double 180 turns: The pure steam flow direction is forced to double 180 turns inducing gravity separation of larger water droplets.
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VAPOR COMPRESSION DISTILLATION

Two circuits supplied by the same water, primary circuit produces distillate from feed water while secondary circuit is responsible for the heat recovery. The feed water enters the system and is heated up in the heat exchanger by the leaving distillate. The energy for evaporation is delivered by the steam of secondary circuit which condensate in the heat exchanger. Large evaporation produces dry steam nearly without droplets; this steam passes the cyclone for last droplets removing by means centrifugal force. The clean steam reaches the condenser and condenses to sterile distillation. The water of secondary circuit evaporates, is taken in by pump and raised to an higher pressure and temperature thus the steam can be used as heating medium for feed water evaporation.
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QUALITY DESIGN OF MATERIAL, FINISHING, CONSTRUCTION AND PROCESS CONTROL, INCLUDED IN THERMOCOMPRESSION WATER STILL SYSTEM
Quenched Waste System SS 304 L cooling spray nozzles, automatic cooling water valve All the SS 316 L material in contact with pure steam have a roughness < 0,6 m Ra All tubing and fittings are welded by orbital machine, wherever technically possible. Welding map and welding report are included Support Frame All components are assembled on a SS 304 Support Frame
SS 316 L Finishing Surfaces
Welding piping, Welding Map and Welding Report
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INTRODUCTION
4. STORAGE AND DISTRIBUTION
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STORAGE AND DISTRIBUTION

Distribution Loop
transport the water to use points (POUs) at the required flow, temperature and pressure.
Storage Tank
supply the facility peak consumptions without the necessity of over sizing the purification system.
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STORAGE TANK
ADVANTAGES
Reserve capacity during purification outage Atmospheric air break for loop return Service of upstream water purification equipment Minimize purification system instantaneous demand capacity Contact tank for ozone sanitization
POTENTIAL DISADVANTAGES
Storage tank capital costs Associated equipment capital costs (pumps, vent filter, instrumentation, etc...) Usually less than water purification equipment size increasing to handle the peak demand
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In order to prevent biofilm contamination, periodic sanitization and continuous circulation of the water are needed.
A tank spray ball is recommended to allow the wetting of the entire internal tank surface.
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TANKS SIZING and DESIGN CONSIDERATION

Criteria affecting storage capacity are users existing and future demand, amount of use, duration, timing and number of POUs simultaneously opened Vessels should be designed and installed using appropriate standards that dont compromise the water quality or system operation Horizontal tanks may be used to address space issues, while vertical orientation is the most common based on the following advantages: Lower cost Less dead volume Simpler spray ball design Less floor space require
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PUMPS
Sanitary centrifugal pumps are commonly employed and designed on flow, pressure, temperature and velocity.
Frequency control device that control the pump motor speed, may be used to maintain a constant internal loop speed in every operating condition
VENT FILTERS
The tank should be vented to allow filling and emptying, and a filter should be used at the vent to avoid microbial contamination. Typically are made in hydrophobic PTFE, PP, or PVDF to prevent wetting. Filters should be capable of withstanding sanitization and sized based on vessel design characteristics
HEAT EXCHANGER
Heat Exchanger equipment is used to heat or cool distributed water to desirable levels or to maintain temperatures.
Equipment part in contact with distributed water should be specified with appropriate materials, finishes and connections.
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DISTRIBUTION LOOP
TUBAZIONI Attrezzature farmaceutiche e sistemi di tubazioni per il PW, HPW, WFI e la distribuzione del vapore puro, devono in acciaio inox AISI 316L, resistente alla corrosione, necessaria a soddisfare le condizioni di funzionamento e metodi di sanificazione. La produzione dei tubi e la installazione devono rispondere alle specifiche norme (ad esempio, ASTM, ASME BPE, ISO, DIN, SMS, BS, JIS-G), oltre ad altri requisiti (21 CFR 211.65). Saldatura automatica il metodo preferito per unire i sistemi di tubazioni di elevata purezza, a causa del maggiore controllo dei parametri critici di saldatura , tuttavia saldatura manuale pu essere richiesto e utilizzato in situazioni specifiche.. I sistemi di stoccaggio e di distribuzione devono essere installati in conformit con cGMP. VALVOLE Valvole a membrana generalmente sono utilizzati in sistemi ad elevata purezza. Altri tipi di valvole, quali valvole a sfera e valvole a spillo , in genere non vengono utilizzati.
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LOOP DIMENSIONAMENTO Il flusso di acqua nella tubazione deve essere di tipo turbolento per controllare lo sviluppo del biofilm sulla parete tubazione. La capacit del sistema dovrebbe essere tale che la quantit desiderata di acqua pu essere utilizzata in qualsiasi momento senza rischiare la perdita di pressione di ritorno. Tipicamente il dimensionamento del loop deve garantire la velocit interna nella tubazione in un range 1 3 m / sec. In ogni condizione di lavoro. PROGETTAZIONE CONSIDERAZIONE considerato pratica comune per consentire il completo svuotamento del circuito di distribuzione per evitare il ristagno di acqua. Rami morti (dead leg) dovrebbero essere ridotti al minimo o eliminati. Una condizione turbolenta pu essere mantenuto se la lunghezza dei tronchetti limitata,non superiore a 3 diametri.
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STRUMENTI Strumentazione appropriata dovrebbe garantire il corretto monitoraggio di un sistema di acqua ad elevata purezza. I componenti possono variare da indicatori visivi locali di dispositivi in grado di integrazione con i sistemi elettronici che offrono il controllo, allarme, trend. I parametri tipici monitorati in acqua farmaceutica sono temperatura, pressione, livello del serbatoio e della conducibilit. Ulteriori parametri possono includere flusso, la velocit della pompa e TOC.
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CONSIDERAZIONI GENERALI Numerosi criteri devono essere considerati quando si valuta progetti alternativi per i sistemi di stoccaggio e distribuzione. I vantaggi / svantaggi di progettazione devono essere conformi ai requisiti utente per l'acqua. La progettazione ottimale di un deposito di acqua farmaceutica e sistema di distribuzione dovrebbe includere le seguenti voci: - Mantenere la qualit chimica e microbica delle acque entro limiti accettabili; - Ridurre al minimo le condizioni e le posizioni che favoriscono la crescita microbica; - Garantire la necessaria portata istantanea a pi punti di utilizzo.; - Ridurre al minimo di capitale e costi operativi; - Considerazione la possibilit di una futura espansione.
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Continuous Circulation?
Distribution Decision Flowchart

Branched/ One Way Distribution
No
Yes
Ozonated Storage and Distribution
Ozone
POU Temperature Required?
Ambient Only
Method of Sanitization?
Heat
Hot or Multiple Temperatures
Chemical
Ambient or Reduced Temperature Storage and Distribution
Hot Storage, Cooled and Reheated Distribution OR Hot Storage, Cooled Bypass Circulating Distribution OR Ambient or Reduced Temperature Storage and Distribution
Hot Usage Only?
Yes
Hot Storage, Hot Distribution
or
Primary/Secondary Distribution (Hot)
No
Limited Quantity of Cooled Use Point
Yes
Hot Distribution, Cooled Branch Use Point, Heat Sanitized
or
Hot Distribution, Cooled Use Point, Slip Stream
No
Hot Distribution, Cooled Sub-Loop
or
Primary/Secondary Distribution (cooled)
or
Parallel Distribution Loops (cooled)
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PW cold Storage and Distribution with Continuous Polishing - Heat sanitizable
Advantages Water quality continuously maintained Can maintain water quality stored over extended periods of low or no use
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Ozonated PW Storage and Distribution
Advantages
Compatible non-metallic material of construction may be considered Excellent microbial control No heat hazards during sanitization Tank and pump continuously sanitized Low cost of operation Return water sanitized in tank Short sanitization time
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WFI Hot Distribution with cooled Use Point, Slip-Stream
Advantages
Can be used for single or multiple cooled, localized use point Use point can be hot or cooled Lower energy consumption than cooling entire loop Continuous flow through slip-stream
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The same configuration can be applied for a cold PW Storage and Distribution system with heated POUs and Thermal Sanitization. The PW should be maintained <15C and greater turbulence in order to minimize bacteria growth and biofilm contamination
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USE POINTS (POUs) CONFIGURATION

characterized for each use point. Each POU should be identified with following proper values Unique identifier (tag) Maximum instantaneous flow rate Periodic consumption requirements (e.g. Daily, weekly) and duration Pressure requirement Temperature requirement Method of delivery (automatic or manual)
In general terms, FLOW RATE is primarily used for sizing distribution lines
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HOW TO DRAWN THE WATER?

The distribution loop topic key in design considerations is minimized, or eliminated where possible, the DEADLEGS. A turbulent condition may be maintained in short dead ended pipe stubs. There are two valve configuration to solve this problem
MINIMUM DEAD LEG (standard valve configuration)
ZERO DEAD LEG VALVE
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The standard valves configuration (Minimum dead leg) will be installed at the minimum distance from the distribution loop in order to minimize the dead legs
The user points valves type butt welds, will be installed directly on the main loop piping in order to avoid dead legs.
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CARICA MICROBICA E BIOFILM CI SONO PROVE SCIENTIFICHE CHE I BATTERI PREFERISCONO VIVERE IN BIOFILM,
Estese indagini su sistemi acquatici hanno dimostrato che oltre il 99% di tutta lattivit microbica avviene in biofilm.Il biofilm definito come cellule batteriche aderenti tra loro e / o alle superfici di contatto e sono ricoperte da una sostanza vischiosa (lipopolisaccaride), che agisce come uno scudo, proteggendo il biofilm da attacchi fisici e chimici. Lo spessore di un biofilm essenzialmente funzione di: - la concentrazione di nutrienti disponibili - velocit dellacqua - regime biocida, - pratiche di sanificazione, ecc
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STRATEGY APPROACHES TO CONTROL BIOFILM

In order to maintain low the biofilm level in compendial water the combination of the following strategies should be considered:
1. Minimization of nutrient concentration in the PW compendial TOC less 100ppb 2. Selection material with internal finishing less 0.6 m Ra to make cleaning easier 3. Maintain high flow rate in the distribution piping > 1m/sec and turbulent flow Reynolds N > 10.000 4. Compendial Water Temperature heated > 85C (WFI) or cooled < 15C (PW) 5. Install U.V. light 254 nm on PW loop 6. Design Continuous PW Storage Tank sanitization by Ozone (O3) and weekly extension of Ozone sanitization to the PW distribution loop 7. Proceed on intermittent sterilization (121C) of WFI storage and distribution loop
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STRATEGY APPROACHES TO CONTROL BIOFILM

Nota: Sterilizzazione del biofilm con, per esempio, il vapore uccidere tutti i batteri presenti, tuttavia, il vapore non rimuove completamente il biofilm (all'occorrenza). Tuttavia, l'asportazione di un biofilm pu essere molto importante, poi che evitta che divente nutriente a sua volta per i nuovi batteri invasori.
sec-min sec-min hours-days days-years
I vantaggi di biocidi (ad esempio, l'ozono) hanno un doppio effetto : indeboliscono le forze dinamica di legame dei batteri tra loro ed alla superficie, riducendo in tal modo le forze di taglio necessari per la loro rimozione del biofilm stesso
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INTRODUCTION
5. VALIDATION ACTIVITIES QUALIFICA DI COMPENDIA WATER
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VALIDATION ACTIVITIES
LA VALIDAZIONE DI UN IMPIANTO cGMP COMPLIANT DEVE STRETTAMENTE SEGUIRE LE SEQUENZE DEFINITE DALLE AUTORITA DI RIFERIMENTO: Usp 35 Eur Pharmacopeias 7.0 cGMP- requirements Guidelines of the drug control authorities (FDA) Gamp 5
LA QUALIFICA DEL SISTEMA ACQUA Le procedure di qualificazione hanno lo scopo di dimostrare che il sistema messo in esercizio produce in modo consistente acqua della qualit di specifica, nelle differenti condizioni, operando secondo le procedure definite. Le procedure di qualifica includono le seguenti fasi: Redazione dei Protocolli di Installation Qualification (IQ); Redazione dei Protocolli di Operational Qualification (OQ); Redazione dei Protocolli di Performance Qualification (PQ).
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Qualifica - IQ
1.1 Qualifica di Installazione IQ Lattivit di IQ consiste nella verifica che il nuovo impianto realizzato, risulti conforme ai documenti di progetto e sia stato correttamente realizzato in accordo con le specifiche di progetto. Il protocollo di IQ dovr indicare con chiarezza e sinteticit le attivit previste per la qualifica dellinstallazione, definendo lo scopo, i prerequisiti, il metodo, le attivit da svolgere in campo, le responsabilit e i criteri di accettabilit. Al termine della qualifica di installazione, ad ogni protocollo dovr corrispondere: Il rapporto della documentazione controllata (disegni, specifiche, schemi) I rapporti per i controlli visivi di installazione relativi alla corrispondenza tra i documenti di progetto e gli impianti realizzati I rapporti relativi ai test fisici di post-installazione(es. test hardware sistemi computerizzati, test di pressatura idraulica, passivazione) Il rapporto finale della qualifica con lelenco di tutti i rapporti e lelenco delle deficienze riscontrate, con le relative azioni di correzione messe in atto
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Qualifica - OQ
1.2 Qualifica di Funzionamento OQ La fase di OQ consiste nella verifica che i sistemi funzionino correttamente e garantiscano risultati in totale accordo alle specifiche funzionali di progetto. Prerequisito per lesecuzione della fase di OQ il completamento positivo della fase IQ. Il protocollo OQ dovr indicare con chiarezza e sinteticit le attivit previste per la qualifica del funzionamento degli impianti, definendo lo scopo, i prerequisiti, il metodo, le azioni, i criteri de accettabilit, il numero di ripetizioni o la durata delle prove e la strumentazione da utilizzarsi. Ad ogni protocollo di IQ dovranno corrispondere: I rapporti relativi alle calibrazioni degli strumenti critici (Instruments calibration Reports) I verbali con i dati relativi alle prove di funzionamento del sistema
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Qualifica - PQ
1.3 Qualifica di Performance - PQ La qualifica di performance si suddivide in tre fasi con obiettivi differenti:
Fase Obiettivi Durata della Fase
Sviluppare gli appositi range operativi Sviluppare e finalizzare le procedure operative, per il cleaning e per la manutenzione Dimostrare che il sistema in grado di produrre acqua della qualit richiesta Dimostrare che limpianto performa allinterno dei range prestabiliti Dimostrare la coerenza tra la qualit dellacqua prodotta e la qualit richiesta Dimostrare che limpianto in grado di mantenere in maniera stabile e a lungo termine i parametri di progetto
24 settimane
24 settimane
1 anno
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Criteri di Accettazione
1.4 Criteri di Accettazione FASE 1 e 2 I risultati ottenuti dalla fase 2 di convalida dovranno rispecchiare landamento dei campionamenti di fase 1 dimostrando lalta qualit dellacqua prodotto dallapparecchio di generazione I parametri indagati dovranno essere conformi alle specifiche USP e EP e ai limiti b pi restrittivi definiti nel protocollo di convalida. Lacqua prodotta dallimpianto dovr dimostrarsi idonea allutilizzo produttivo. FASE 3 I risultati ottenuti dovranno rispecchiare landamento dei campionamenti di fase 2 dimostrando lalta qualit dellacqua prodotta. I parametri indagati dovranno essere conformi alle specifiche USP e EP e ai limiti pi restrittivi definiti nel protocollo di convalida. Lacqua prodotta dallimpianto dovr dimostrarsi idonea allutilizzo produttivo. Dopo le attivit di convalida vengono convalidate la frequenza delle attivit di sanitizzazione / sterilizzazione del reparto produzione, le frequenze delle attivit di sanitizzazione / sterilizzazione del reparto stoccaggio e distribuzione e vengono meglio precisati gli Alert e Action Limit.
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INTRODUCTION
6. COMPARISON COMPENDIA
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COMPARISON COMPENDIA
COMPARAZIONE COMPENDIAL WATER ANVISA versusUSP35 - EP7

USP 35
United States Pharmacopeia
Compendial Water
EP 7th Ed
European Pharmacopoeia
Purified Water Water for Injection Highy Purified Water 4.3 S/cm @ 20C 5.1 S/cm @ 25C
Multiple Effect Still Vapor Compression Still MANDATORY.
ANVISA
Agncia Nacional de Vigilncia Sanitria
Purified Water Water for Injection
Purified Water Water for Injection
PW Conductivity
1.1 S/cm @ 20C 1.3 S/cm @ 25C

Multiple Effect Still Vapor Compression Still Double Pass RO
1.1 S/cm @ 20C 1.3 S/cm @ 25C

Multiple Effect Still Vapor Compression Still RECOMMENDED
WFI Generation Methods
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Highy Purified Water

The definition of HPW makes it an alternative to WFI in those processes where the quality of WFI is desirable, but not required.
The quality attributes of HPW are the same as the quality attributes of EP WFI, but distillation is not a required final treatment process. Typical production methods include one more unit process compared to production of PW Advantages: generally less expensive than WFI generally chemical free method generally low operating costs Disadvantages: cannot replace WFI in all applications, for ex.: large volume parenterals
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WFI Generation Methods

Today the use of Reverse Osmosis to prepare WFI is considered acceptable by the USP but non by the EP
EP is mandactory and ANVISA Recommend that WFI to be prepared by distillation
THE MAJOR OBJECTION ARE:
RANGE of SEPARATION for Reverse Osmosis

VALIDATION and MAINTENANCE of devices MICROBIOLOGICAL ASPECTS Biofilm formation on both sides RO membranes
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COMPARISON COMPENDIA ANVISA

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1

WORKSHOP May 20th 2013 ACQUA PER USO FARMACEUTICO

La selezione della qualit necessaria per l'acqua o vapore puro

potenzialmente la fase pi critica

PHARMACEUTICAL WATER QUALITY DECISION TREE

Control of fouling :rimozione della torbidit e colloidi

Control of fouling :rimozione della torbidit e particolati TORBIDITA

I metodi pi utilizzati per rimuovere TORBIDITA E PARTICOLATO,sono: Filtrazione multimedia Ultrafiltrazione

Large capacity per unit cost Low cost of operation

Particle reduction limited to 10m (approx)

Can become a source of microbiological contamination if improperly maintained, designed or operated

CASE STUDY: Laboratrio Teuto Brasileiro

IMPATTANDO DRAMMATICAMENTE SULLE MEMBRANE DI OSMOSI INVERSA CAUSANDO LA

Chemically Enhanced Backwash (CEB) step

Air Scour Step

Control of scaling :controllo della durezza

I sistemi di controllo includono METHODS of CONTROL include :

- Addolcimento con resine a scambio ionico - Dosaggio di prodotti antiprecipitanti(antiscalant)

Softening by Ion Exchange

Na+, HCO3-, Cl-, NO3-, K+ , SO42-, SiO2

Softening by Ion Exchange

Operating Temperatures below 15C avoid the bacterial growth

DEBATERIZAZIONE RAGGI ULTRAVIOLETTI (UV)

3. FINAL TRATMENT OPTIONS

FINAL TREATMENT OPTIONS - NON-COMPENDIAL WATER and COMPENDIAL PURIFIED WATER

another Reverse Osmosis Pass RO + RO

a continuous electrodeionization stage RO + EDI

FINAL TREATMENT OPTIONS - NON-COMPENDIAL WATER and COMPENDIAL PURIFIED WATER

FINAL TREATMENT OPTIONS - NON-COMPENDIAL WATER and COMPENDIAL PURIFIED WATER

REVERSE OSMOSIS LIMITATIONS

FINAL TREATMENT OPTIONS - NON-COMPENDIAL WATER and COMPENDIAL PURIFIED WATER

FINAL TREATMENT OPTIONS - NON-COMPENDIAL WATER and COMPENDIAL PURIFIED WATER

HYDROPHOBIC HOLLOW FIBER MEMBRANE

Disadvantages more expensive than sodium hydroxide dosing

FINAL TREATMENT OPTIONS - NON-COMPENDIAL WATER and COMPENDIAL PURIFIED WATER

SODIUM HYDROXIDE DOSING SYSTEM

FINAL TREATMENT OPTIONS - NON-COMPENDIAL WATER and COMPENDIAL PURIFIED WATER

FINAL TREATMENT OPTIONS - NON-COMPENDIAL WATER and COMPENDIAL PURIFIED WATER

FINAL TREATMENT OPTIONS - NON-COMPENDIAL WATER and COMPENDIAL PURIFIED WATER

CONTROL AND INSTRUMENTATION

The most important parameters to control and measure are

FINAL TREATMENT OPTIONS - NON-COMPENDIAL WATER and COMPENDIAL PURIFIED WATER

REVERSE OSMOSIS CONCENTRATE REUSE

TOTAL RECOVERY = 71,4%

1,2 m3/h 0,5 m3/h

RO DOUBLE PASS SYSTEM WITHOUT CONCENTRATE RECOVERY SYSTEM (CRS)

FINAL TREATMENT OPTIONS - NON-COMPENDIAL WATER and COMPENDIAL PURIFIED WATER

TOTAL RECOVERY = 87,7%

CONCENTRATE RECOVERY SYSTEM

= 65% 0,42 m3/h

RO DOUBLE PASS SYSTEM WITH CONCENTRATE RECOVERY SYSTEM (CRS)

FINAL TREATMENT OPTIONS - NON-COMPENDIAL WATER and COMPENDIAL PURIFIED WATER

RO MEMBRANE CLEANING IS NEEDED

FINAL TREATMENT OPTIONS - NON-COMPENDIAL WATER and COMPENDIAL PURIFIED WATER

FINAL TREATMENT OPTIONS - NON-COMPENDIAL WATER and COMPENDIAL PURIFIED WATER

ULTRAVIOLET LIGHT TREATMENT

UV wavelengths and intensity level required depend on the expected function

FINAL TREATMENT OPTIONS

WATER FOR INJECTION WFI

FINAL TREATMENT OPTIONS

WATER FOR INJECTION (WFI)

FINAL TREATMENT OPTIONS

WATER FOR INJECTION (WFI)