Download - Workshop May 20th 2013 (2)
WORKSHOP May 20th 2013
ACQUA PER USO FARMACEUTICO
Speaker
Pasquale Della Valle ELETTRACQUA Technical and Sales Manager
1
WORKSHOP May 20th 2013
WATER FOR PHARMACEUTICAL PURPOSES
1. Introduzione
AGENDA
2
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.
1. INTRODUZIONE
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INTRODUCTION
INTRODUZIONE
La selezione della qualità necessaria per l'acqua o vapore puro
è potenzialmente la fase più 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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L’uso dell’Acqua nel settore farmaceutico include le seguenti applicazioni :
- Come ingrediente nella formulazione di specialità 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 l’industria farmaceutica rappresenta una importante sfida poiché deve essere conforme alle prescrizioni delle cCMP,oltre che rispettare tutte le leggi e le regolatorie locali.
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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 d’acqua.In ogni
caso la scelta finale della qualità dell’acqua in relazione all’impiego al quale è destinata,resta di specifica responsabilittà della Azienda Farmaceutica .
Le acque di uso farmaceutico sono divise in due categorie:
Compendial water e Non compendial water
INTRODUZIONE
Le pharmacopee più importanti:
• United States Pharmacopoeia (USP),
• European Pharmacopoeia (EP)
• Japanese Pharmacopoeia (JP)
Definisco due Compendial Water and Steam
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Purified Water (PW)
Water far Injection (WFI)
Pure Steam (PS)
Highly Purified Water(HPW),EU only
INTRODUZIONE
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AC
EU
TIC
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INTRODUZIONE
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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 qualità dell'acqua di alimentazione, e gli attributi di qualità per le acque compendial sono
definite nelle specifiche monografiche.
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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INTRODUZIONE
2. PRETREATMENT OPTION
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INTRODUCTION
Pretrattamento viene definito l’insieme di tutte le fasi di trattamento necessarie a garantire che la qualità dell'acqua di alimentazione
diventi di qualità adeguata ad ottimizzare le prestazioni del trattamento finale.Esse sono
definiti nei seguenti step.
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Control of fouling :rimozione della torbidità e colloidi
Control of scaling :rimozione o controllo della durezza e metalli
Control of Organics:riduzione delle sostanze organiche e batteriche
PRETREATMENT OPTION
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Control of fouling :rimozione della torbidità e particolati
PARTICOLATI
Tipicamente sono minerali insolubili. In particolare silice coloidale.
TORBIDITA’
È causata da materiale in sospensione e colloidale, che può essere di natura organica o inorganica ed altri microorganismi .
PRETREATMENT OPTION
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La rimozione della torbidita’ e particolato è fondamentale per evitare lo sporcamento dello step finale del trattamento, in
particolare l’intasamento delle membrane di Osmosi Inversa
I metodi più utilizzati per rimuovere la TORBIDITA’ E PARTICOLATO,sono:
• Filtrazione multimedia
• Ultrafiltrazione
PRETREATMENT OPTION
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ILT
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PE
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Filtrazione Dualmedia :sono formati da contenitori in pressione,con all’interno materiale filtrante formato da quarzite e carbone antracite.
Advantage: • Large capacity per unit cost • Low cost of operation
Disadvantage: • Particle reduction
limited to 10µm (approx) • Can become a source of
microbiological contamination if improperly maintained, designed or operated
PRETREATMENT OPTION
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Ultrafiltration
Vantaggi : • La Ultrafiltrazione è una barriera
invalicabile per tutti microorgnismi (virus e batteri) e tutti quei composti che formanno la torbidittà oltre che per la totalittà dei colloidi. L’efficacia del processo della filtrazione è indipendente della caratteristica dell’acqua 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.
PRETREATMENT OPTION
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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 è limitato a circa 10μm, 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 affidabilità dovuta al fatto che tutta la torbidita’ ed i colloidi saranno stati completamente eliminati. .
PRETREATMENT OPTION
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CASE STUDY:
Laboratório Teuto Brasileiro
PROBLEMATICHE DELL’ACQUA 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
PRETREATMENT OPTION
Sostituizione delle membrane circa 6 mesi con notevole costo di essercicio e fuori servizio di produzione
PROBLEMATICHE RILEVATE SULL’ IMPIANTO PRE ESISTENTE,FORNITO DA ALTRO SUPPLIER DA 7/8 ANNI
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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
L’ACQUA 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
PRETREATMENT OPTION
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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 (0,03µ nominal pore) for excellent removal of particulate matter and bacteria, and most viruses and colloids.
PRETREATMENT OPTION
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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.
VIRUS BACTERIA
IN
IN
FIL
TR
AT
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PRETREATMENT OPTION
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Air
Sc
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tep
Cleaning Step The frequency of the cleaning step dependent on the feed water quality
Ba
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wa
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(B
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Ste
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B
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(C
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Cle
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Pla
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Cle
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(C
IP)
Ste
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PRETREATMENT OPTION
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Control of scaling :controllo della durezza
METHODS of CONTROL include :
- Addolcimento con resine a scambio ionico
- Dosaggio di prodotti antiprecipitanti(antiscalant)
Il controllo della durezza(Ca+Mg) è necessario per evitare la precipitazione di composti incrostanti,come carbonati sulle membrane di Osmosi Inversa.
I sistemi di controllo includono
PRETREATMENT OPTION
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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 %
Regenerant Waste
SAC
Na+, HCO3
-, Cl-, NO3-,
K+ , SO42-, SiO2
PRETREATMENT OPTION
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Softening by Ion Exchange
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)
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
PRETREATMENT OPTION
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Antiscalant Dosing
L’Antiscalant sono dei composti chimici organo’fosfonati, a elevatissimo peso molecolare
L’antiscalant, dosato in piccola quantittà 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 solubilittà,quindi questi composti chimici,restano perfettamente in soluzione nell’acqua e vengono totalmente rigettati delle membrane di Osmosi Inversa senza che vengono contaminate
APPROVATI by FDA-EPA-EP-WHO
PRETREATMENT OPTION
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SANITIZAZIONE
I necessarie metodi di santizazione per evitare eccessiva crescittà microbica sono : • Sanitizazione chimica,oppure termica • Controllo di Temperatura,a valori inferiori a 18°C
Periodic Hot Water Sanitization Temperatures above 80°C result the complete killing of all non-resistant bacteria.
> 80°C
15°C
Operating Temperatures below 15°C avoid the bacterial growth
PRETREATMENT OPTION
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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.
DEBATERIZAZIONE RAGGI ULTRAVIOLETTI (UV)
PRETREATMENT OPTION
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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.
PRETREATMENT OPTION
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IPOCLORITO DI SODIO
Deve essere totalmente eliminato prima di alimentare le membrane di Osmosi Inversa, che essendo di materiale
Poliamide vereberro iremediabilmente ossidate.
PRETREATMENT OPTION
PRINCIPALI SISTEMI DI RIMOZIONE IPOCLORITO DI SODIO:
• Activated Carbon
• Reduction with Sodium Bisulfate dosing
3. FINAL TRATMENT OPTIONS
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INTRODUCTION
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FINAL TREATMENT OPTIONS - NON-COMPENDIAL WATER and COMPENDIAL PURIFIED WATER
The most common PW system design implement a Single Reverse Osmosis Pass with
another Reverse Osmosis Pass
RO + RO
a continuous electrodeionization stage
RO + EDI
or
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
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PERMEATE FLOW
PERMEATE
FEED WATER
CONCENTRATE
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.
Advantages • highest rejection of contaminants • operate effectively at lower temperatures
(4°C 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
CONCENTRATE
FINAL TREATMENT OPTIONS - NON-COMPENDIAL WATER and COMPENDIAL PURIFIED 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.
FINAL TREATMENT OPTIONS - NON-COMPENDIAL WATER and COMPENDIAL PURIFIED WATER
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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.
FINAL TREATMENT OPTIONS - NON-COMPENDIAL WATER and COMPENDIAL PURIFIED WATER
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Liquid Inlet
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.
Advantages simple design and maintenance
chemical free method simple installation low operation costs
Disadvantages more expensive than
sodium hydroxide dosing
FINAL TREATMENT OPTIONS - NON-COMPENDIAL WATER and COMPENDIAL PURIFIED WATER
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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.
FINAL TREATMENT OPTIONS - NON-COMPENDIAL WATER and COMPENDIAL PURIFIED WATER
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FINAL TREATMENT OPTIONS - NON-COMPENDIAL WATER and COMPENDIAL PURIFIED WATER
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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FINAL TREATMENT OPTIONS - NON-COMPENDIAL WATER and COMPENDIAL PURIFIED WATER
RO PERFORMANCE Single pass RO typically reduce the contaminants more than 99%, but produced water don’t 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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FINAL TREATMENT OPTIONS - NON-COMPENDIAL WATER and COMPENDIAL PURIFIED WATER
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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FINAL TREATMENT OPTIONS - NON-COMPENDIAL WATER and COMPENDIAL PURIFIED WATER
REVERSE OSMOSIS CONCENTRATE REUSE Pretreated Water
BREAK TANK
FIRST PASS RO γ = 75%
SECOND PASS RO γ = 85%
4,2 m3/h
0,5 m3/h
4,7 m3/h
1,2 m3/h
3,5 m3/h
3 m3/h
RO DOUBLE PASS SYSTEM WITHOUT CONCENTRATE RECOVERY SYSTEM (CRS)
TOTAL RECOVERY γ = 71,4%
0,5 m3/h
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FINAL TREATMENT OPTIONS - NON-COMPENDIAL WATER and COMPENDIAL PURIFIED WATER
Pretreated Water
BREAK TANK
FIRST PASS RO γ = 75%
3,42 m3/h
1,28 m3/h
4,7 m3/h
1,2 m3/h
3,5 m3/h
3 m3/h
RO DOUBLE PASS SYSTEM WITH CONCENTRATE RECOVERY SYSTEM (CRS)
CONCENTRATE RECOVERY SYSTEM
γ = 65%
0,42 m3/h
0,5 m3/h
0,78 m3/h
1,28 m3/h
TOTAL RECOVERY γ = 87,7%
SECOND PASS RO γ = 85%
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FINAL TREATMENT OPTIONS - NON-COMPENDIAL WATER and COMPENDIAL PURIFIED WATER
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
Salt passage increasing
Differential pressure exceeding 2,5 bar
Product flow rate decreasing
THERMAL CLEANING
Carry out by Hot Water at 85°C Specially constructed membranes are needed
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FINAL TREATMENT OPTIONS - NON-COMPENDIAL WATER and COMPENDIAL PURIFIED WATER
CONTINUOUS ELECTRODEIONIZATION
CEDI
ION EXCHANGE RESINS
ION SELECTIVE MEMBRANE
ELECTRICAL FIELD to continuously remove ionized species
and regenerate the resins
+
+
=
Continuous, not in batch or intermittent
Ionic transport properties of the ion exchange are primary sizing parameter
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FINAL TREATMENT OPTIONS - NON-COMPENDIAL WATER and COMPENDIAL PURIFIED WATER
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.
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 µS/cm or
lower.
CEDI unit performance is a function of feed water quality.
ANODE CATODE
FEEDING WATER
Co
nc
en
tra
te
Co
nc
en
tra
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Co
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en
tra
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Co
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PU
RIF
IED
W
AT
ER
PU
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IED
W
AT
ER
PU
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IED
W
AT
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FINAL TREATMENT OPTIONS - NON-COMPENDIAL WATER and COMPENDIAL PURIFIED WATER
ULTRAVIOLET LIGHT TREATMENT for Polishing and Removal of specific contaminants
UV light treatment aims to decrease the bacteria
growth inside the treated 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
UV wavelengths and intensity level required depend on the expected
function
185 nm units are used for TOC (Total
Organic Carbon) reduction
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
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FINAL TREATMENT OPTIONS
WATER FOR INJECTION
WFI
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FINAL TREATMENT OPTIONS – WATER FOR INJECTION (WFI)
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FINAL TREATMENT OPTIONS – WATER FOR INJECTION (WFI)
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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FINAL TREATMENT OPTIONS – WATER FOR INJECTION (WFI)
BASIS FOR ECONOMIC COMPARISON
The three primary factors affecting the operating costs of any still design are
INDUSTRIAL STEAM
ELECTRICITY COOLANT
CONSUMPTION
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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FINAL TREATMENT OPTIONS – WATER FOR INJECTION (WFI)
CONTRUCTION MATERIALS and SURFACE FINISHING
The recommended material for the equipment is Stainless Steel AISI 316L, finishing Ra ≤ 0,6 µm, 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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FINAL TREATMENT OPTIONS – WATER FOR INJECTION (WFI)
COOLING WATER
FEEDING PURIFIED WATER
PURE STEAM
WFI
OFF-SPEC WFI
CONDENSATE
INDUSTRIAL STEAM
PURE STEAM
PURE STEAM CONDENSE
CONDENSATE LIQUID DISCHARGE
CONDENSATE DISCHARGE
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FINAL TREATMENT OPTIONS – WATER FOR INJECTION (WFI)
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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FINAL TREATMENT OPTIONS – WATER FOR INJECTION (WFI)
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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FINAL TREATMENT OPTIONS – WATER FOR INJECTION (WFI)
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 ÷ 175°C
Capacit
y
lt/h
Steam Consumption
kg/h
Effects number
4 5 6 7
2.300 783 630 528 456
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FINAL TREATMENT OPTIONS – WATER FOR INJECTION (WFI)
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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FINAL TREATMENT OPTIONS – WATER FOR INJECTION (WFI)
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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FINAL TREATMENT OPTIONS – WATER FOR INJECTION (WFI)
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
SS 316 L Finishing Surfaces
All the SS 316 L material in contact with pure steam have a roughness < 0,6 µm Ra
Welding piping, Welding Map and Welding Report
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
4. STORAGE AND DISTRIBUTION
60
INTRODUCTION
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STORAGE AND DISTRIBUTION
Storage Tank supply the facility peak
consumptions without the necessity of over sizing the
purification system.
Distribution Loop transport the water to use points (POUs) at the required flow, temperature and pressure.
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STORAGE AND DISTRIBUTION
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STORAGE AND DISTRIBUTION
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
STORAGE TANK
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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STORAGE AND DISTRIBUTION
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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STORAGE AND DISTRIBUTION
TANKS SIZING and DESIGN CONSIDERATION
Criteria affecting storage capacity are user’s 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 don’t 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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STORAGE AND DISTRIBUTION
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STORAGE AND DISTRIBUTION
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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STORAGE AND DISTRIBUTION
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 è 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 può essere richiesto e utilizzato in situazioni specifiche.. I sistemi di stoccaggio e di distribuzione devono essere installati in conformità 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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STORAGE AND DISTRIBUTION
LOOP DIMENSIONAMENTO Il flusso di acqua nella tubazione deve essere di tipo turbolento per controllare lo sviluppo del biofilm sulla parete tubazione. La capacità del sistema dovrebbe essere tale che la quantità desiderata di acqua può essere utilizzata in qualsiasi momento senza rischiare la perdita di pressione di ritorno. Tipicamente il dimensionamento del loop deve garantire la velocità interna nella tubazione in un range 1 ÷ 3 m / sec. In ogni condizione di lavoro. PROGETTAZIONE CONSIDERAZIONE È 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 può essere mantenuto se la lunghezza dei tronchetti è limitata,non superiore a 3 diametri.
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STORAGE AND DISTRIBUTION
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 conducibilità. Ulteriori parametri possono includere flusso, la velocità della pompa e TOC.
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STORAGE AND DISTRIBUTION
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 qualità 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 più punti di utilizzo.; - Ridurre al minimo di capitale e costi operativi; - Considerazione la possibilità di una futura espansione.
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STORAGE AND DISTRIBUTION
Continuous Circulation?
POU Temperature
Required?
Hot Usage Only?
Limited Quantity of Cooled Use
Point
Method of Sanitization?
Hot Distribution, Cooled Sub-Loop
Primary/Secondary Distribution (cooled)
Hot Distribution, Cooled Branch Use
Point, Heat Sanitized
Parallel Distribution Loops (cooled)
Hot Distribution, Cooled Use Point,
Slip Stream
Hot Storage, Hot Distribution
Primary/Secondary Distribution (Hot)
Branched/ One Way Distribution
Ambient or Reduced Temperature Storage and
Distribution
Ozonated Storage and Distribution
Hot Storage, Cooled and Reheated Distribution
OR Hot Storage, Cooled Bypass
Circulating Distribution OR
Ambient or Reduced Temperature Storage and
Distribution
No
No
No
Yes
Yes
Yes
or or
or
or
Heat
Ozone
Chemical
Ambient Only
Hot or Multiple Temperatures
Distribution Decision Flowchart
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STORAGE AND DISTRIBUTION
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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STORAGE AND DISTRIBUTION
Ozonated PW Storage and Distribution
Advantages
Compatible non-metallic material of construction may be considered
Tank and pump continuously sanitized
Excellent microbial control Low cost of operation
No heat hazards during sanitization Return water sanitized in tank
Short sanitization time
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STORAGE AND DISTRIBUTION
WFI Hot Distribution with cooled Use Point, Slip-Stream
Advantages
Can be used for single or multiple cooled, localized use point
Lower energy consumption than cooling entire loop
Use point can be hot or cooled Continuous flow through slip-stream
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STORAGE AND DISTRIBUTION
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 <15°C and greater turbulence in order to minimize
bacteria growth and biofilm contamination
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STORAGE AND DISTRIBUTION
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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STORAGE AND DISTRIBUTION
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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STORAGE AND DISTRIBUTION
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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STORAGE AND DISTRIBUTION
Estese indagini su sistemi acquatici hanno dimostrato che oltre il 99% di tutta l’attività microbica avviene in biofilm.Il biofilm è 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 è essenzialmente funzione di: - la concentrazione di nutrienti disponibili - velocità dell’acqua - regime biocida, - pratiche di sanificazione, ecc
CARICA MICROBICA E BIOFILM CI SONO PROVE SCIENTIFICHE CHE I BATTERI PREFERISCONO VIVERE IN BIOFILM,
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STORAGE AND DISTRIBUTION
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 µm 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 > 85°C (WFI) or cooled < 15°C (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 (121°C) of WFI storage and distribution loop
STRATEGY APPROACHES TO CONTROL BIOFILM
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STORAGE AND DISTRIBUTION
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 può 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
5. VALIDATION ACTIVITIES
QUALIFICA DI COMPENDIA WATER
83
INTRODUCTION
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
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VALIDATION ACTIVITIES
• 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 qualità 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).
Qualifica - IQ • 1.1 Qualifica di Installazione – IQ
• L’attività 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 dovrà indicare con chiarezza e sinteticità le attività previste per la qualifica dell’installazione, definendo lo scopo, i prerequisiti, il metodo, le attività da svolgere in campo, le responsabilità e i criteri di accettabilità.
• Al termine della qualifica di installazione, ad ogni protocollo dovrà 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 l’elenco di tutti i rapporti e l’elenco 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 l’esecuzione della fase di OQ è il completamento positivo della fase IQ.
• Il protocollo OQ dovrà indicare con chiarezza e sinteticità le attività previste per la qualifica del funzionamento degli impianti, definendo lo scopo, i prerequisiti, il metodo, le azioni, i criteri de accettabilità, 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
Fase Obiettivi Durata della Fase
1 - Sviluppare gli appositi range operativi - Sviluppare e finalizzare le procedure operative, per
il cleaning e per la manutenzione - Dimostrare che il sistema è in grado di produrre
acqua della qualità richiesta
2÷4 settimane
2 - Dimostrare che l’impianto performa all’interno dei range prestabiliti
- Dimostrare la coerenza tra la qualità dell’acqua prodotta e la qualità richiesta
2÷4 settimane
3 - Dimostrare che l’impianto è in grado di mantenere in maniera stabile e a lungo termine i parametri di progetto
1 anno
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1.3 Qualifica di Performance - PQ
La qualifica di performance si suddivide in tre fasi con obiettivi differenti:
Criteri di Accettazione
88
• 1.4 Criteri di Accettazione
• FASE 1 e 2
• I risultati ottenuti dalla fase 2 di convalida dovranno rispecchiare l’andamento dei campionamenti di fase 1 dimostrando l’alta qualità dell’acqua prodotto dall’apparecchio di generazione
• I parametri indagati dovranno essere conformi alle specifiche USP e EP e ai limiti b più restrittivi definiti nel protocollo di convalida.
• L’acqua prodotta dall’impianto dovrà dimostrarsi idonea all’utilizzo produttivo.
• FASE 3
• I risultati ottenuti dovranno rispecchiare l’andamento dei campionamenti di fase 2 dimostrando l’alta qualità dell’acqua prodotta.
• I parametri indagati dovranno essere conformi alle specifiche USP e EP e ai limiti più restrittivi definiti nel protocollo di convalida.
• L’acqua prodotta dall’impianto dovrà dimostrarsi idonea all’utilizzo produttivo.
• Dopo le attività di convalida vengono convalidate la frequenza delle attività di sanitizzazione / sterilizzazione del reparto produzione, le frequenze delle attività di sanitizzazione / sterilizzazione del reparto stoccaggio e distribuzione e vengono meglio precisati gli Alert e Action Limit.
6. COMPARISON COMPENDIA
89
INTRODUCTION
COMPARAZIONE COMPENDIAL WATER
ANVISA versusUSP35 - EP7
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COMPARISON COMPENDIA
USP 35 United States Pharmacopeia
EP 7th Ed European
Pharmacopoeia
ANVISA Agência Nacional de
Vigilância Sanitária
•Purified Water •Water for Injection
•Purified Water •Water for Injection •Highy Purified Water
•Purified Water •Water for Injection Compendial
Water
≤ 1.1 µS/cm @ 20°C ≤ 1.3 µS/cm @ 25°C
≤ 4.3 µS/cm @ 20°C ≤ 5.1 µS/cm @ 25°C
PW Conductivity
•Multiple Effect Still •Vapor Compression Still •Double Pass RO
•Multiple Effect Still •Vapor Compression Still MANDATORY.
WFI Generation
Methods
•Multiple Effect Still •Vapor Compression Still •RECOMMENDED
≤ 1.1 µS/cm @ 20°C ≤ 1.3 µS/cm @ 25°C
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COMPARISON COMPENDIA
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.
Advantages: • generally less expensive than WFI • generally chemical free method • generally low operating costs
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
Disadvantages: • cannot replace WFI in all
applications, for ex.: large volume parenterals
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COMPARISON COMPENDIA
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
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COMPARISON COMPENDIA – ANVISA