PHARMACEUTICAL Pure Water Guide

WATER TECHNOLOGIES PHARMACEUTICAL PURE WATER GUIDE

04 Introduction 06 Methods of water purification 17 Purified water 18 Water for Injection (WFI) 19 Monitoring the purity of compendial water 21 Water purity standards 23 Maintenance of compendial systems 24 Purified water applications 26 Pure water – hints and tips 27 Glossary of terms 31 Service and maintenance 32 Pharmaceutical purified water process

An overview of water purification techniques in the pharmaceutical industry

Veolia Water Technologies specialises in delivering solutions to service all your process water needs. We are committed to providing process water treatment systems and service to the pharmaceutical, scientific and healthcare sectors. Founded in 1853, with our water treatment experience, focused approach and in-depth knowledge, backed by exemplary customer service, means we can expertly guide your business by delivering process water solutions that meet your needs, giving you peace of mind every time.

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INTRODUCTION

In today’s pharmaceutical facilities the availability of purified water is essential. While the domestic consumer considers tap water to be “pure”, the pharmaceutical end-user regards it as grossly contaminated.

Within the pharmaceutical industry, water is most commonly used in liquid form, not only as an ingredient in many formulations but also as a cleaning agent. Production of Purified Water - pyrogen-free Water, Water for Injection (WFI) and Clean Steam to international pharmaceutical standards is widely recognised as a critical process.

POTABLE WATER contrast, water from an underground Colloidal particles, which can be source generally has a high level organic or inorganic, give rise to haze Purified water used in pharmaceutical of salts and hardness but a low or turbidity in the water. processes is usually produced in-situ organic content. River sources are from local potable water which has intermediate in quality but also often Suspended particles can foul been produced by the treatment of contain products from industrial, reverse osmosis membranes and natural water sources. agricultural and domestic activities. electrodeionization stacks, as well as Seasonal variations in water quality interfere with the operation of valves The unique ability of water to are most apparent in surface waters. and meters. dissolve, to some extent, virtually During the autumn and winter every chemical compound and months, dead leaves and decaying Dissolved inorganic support practically every form of life plants release large quantities of compounds means that potable water supplies organic matter into streams, lakes Inorganic substances are the major contain many substances in solution and reservoirs. As a result, organic impurities in water. They include: or suspension. contamination in surface waters � Calcium and magnesium salts reaches a peak in winter, and falls to a which cause ‘temporary’ or Variations in raw water quality minimum in summer. Ground waters ‘permanent’ hardness Unlike other raw materials, potable are much less affected by the seasons. � Carbon dioxide, which dissolves water varies significantly in purity in water to give weakly acidic both from one geographical region The quality and characteristics of the carbonic acid to another and from season to potable water supply have an important � Sodium salts season. Water derived from an bearing on the purification regime � Silicates leached from sandy river upland surface source, for instance, required to produce purified water. beds usually has a low content of dissolved � Ferrous and ferric iron compounds salts and is relatively soft, but has Suspended particles derived from minerals and rusty a high concentration of organic Suspended matter in water includes iron pipes contamination, much of it colloidal. By silt, pipework debris and colloids. � Chlorides from saline intrusion

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� Aluminium from dosing chemicals Measuring impurities in and minerals potable water � Phosphates from detergents In order to design or select a water � Nitrates from fertilisers purification system it is necessary to have information on the composition Dissolved organic compounds of the feedwater, usually local potable Organic impurities in water arise water. Average data can often be from the decay of vegetable matter, obtained from the local water principally humic and fulvic acids, supplier, however, an analysis of the and from farming, paper making and water gives the information directly. domestic and industrial waste. These include detergents, fats, oils, solvents The filter-blocking potential of and residues from pesticides and the water can be estimated using herbicides. In addition, water-borne a fouling index (FI) test or, less organics may include compounds reliably, turbidity. A wide range leached from pipework, tanks and of methods are available for purification media. determining inorganic components. Ion chromatographic, ICP-mass Microorganisms spectrometric or spectrophotometric The chief microorganisms of concern methods are often used. Electrical for water purification systems are conductivity provides a guide bacteria. A typical bacterial level for a to potential problems. Organic potable pharmaceutical water supply compounds can be determined is ten colony forming units per one individually, e.g. chromatographically, hundred milliliter (10 CFU/100ml) or or an overall indication of organic less. Bacteria are usually kept at these content can be provided by a total low levels by the use of residual levels organic carbon (TOC) measurement. of chlorine or other disinfectants. Total viable bacterial counts as well Once the disinfectants are removed as those of individual species can be during purification, bacteria have the measured by filtration or inoculation chance to proliferate. and incubation in a suitable growth medium. Dissolved gases Potable water is in equilibrium with Total dissolved solids (TDS) is the the air and so contains dissolved residue in ppm obtained by the oxygen and carbon dioxide. Carbon traditional method of evaporating dioxide behaves as a weak acid and a water sample to dryness and uses the capacity of anion exchange heating at 180°C. By far the greatest resins. Dissolved oxygen is usually proportion of the filtered residue only an issue where bubble formation is inorganic salts and TDS is used is a problem. In applications where as an indicator of the total level of the purified water is used in open inorganic compounds present. It can containers it will rapidly re-equilibrate be measured directly or estimated by with the gases in the air. multiplying the conductivity of the water in μS/cm at 25°C by 0.7.

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METHODS OF WATER PURIFICATION

Purifying potable water sufficiently primarily effective in killing planktonic solids and to protect downstream for use in the pharmaceutical (free-floating) microorganisms. purification technologies from industry usually requires a series Sloughing biofilm and byproducts fouling and clogging. They are of purification stages. The overall of microorganism growth and replaced periodically. objective is to remove the impurities metabolism (e.g. endotoxins) are always in the feedwater while minimising potential contaminants of water. additional contamination from the components of the purification The challenges for a purified water system and from bacterial growth. generation system are to: System design and component � Meet all of the requirements selection are critical to success. for U.S. and/or European Pharmacopoeia Monographs The selection of the initial stages of � Remove the bacteria present in the a purification system will depend feedwater on the characteristics of the � Prevent bacteria from entering feedwater. The primary purpose of the system and causing the pretreatment stages is to reduce re-contamination damage to subsequent components, � Inhibit the growth of bacteria to ensure reliable operation of the in the system by design and by water purification system, and to periodic sanitisation Activated carbon (AC) decrease the cost of operation by Activated carbon is used in preventing excessively frequent PRETREATMENT pretreatment to remove chlorine and replacement of more expensive chloramine from feedwater so they components. Microporous depth filters do not damage membrane filters and Microporous depth filters provide ion exchange resins. Bacteria a physical barrier to the passage of Microorganisms and their byproducts particles, and are characterised by Most activated carbon is produced are a particular challenge. nominal particle size ratings. Depth by activating charcoal from coconut Microorganisms will enter an filters are matted fibre or material shells or coal by roasting at 800 – unprotected water purification compressed to form a matrix 1,000°C in the presence of water system from the feedwater, any that retains particles by random vapour and CO2. Acid washing openings in the system, or through adsorption or entrapment. Most raw removes much of the residual oxides the point of use. They will grow as waters contain colloids, which have a and other soluble material. Activated biofilms on all the wetted surfaces slight negative charge (measured by carbon used in water treatment of water purification components, the Zeta potential). Filter performance usually has pore sizes ranging from including storage tanks and the can be enhanced by using micro 500-1,000 nm and a surface area plumbing of a distribution system. filters that incorporate a modified of about 1,000 square meters per A biofilm is a layer composed surface, which will attract and retain gram. Carbon is used as granules mostly of glycoproteins and these naturally occurring colloids, or moulded and encapsulated heteropolysaccharides in which which are generally much smaller cartridges which produce fewer fine bacteria can multiply even when than the pore sizes in the membrane. particles. the concentration of nutrients in the water is very low. The layer also Depth filters (typically 1-50 μm) are Activated carbon reacts chemically protects the organisms from periodic commonly used as an economical with 2-4 times its weight of chlorine, treatment with biocides that are way to remove the bulk of suspended producing chlorides. This reaction is

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very rapid and small carbon filters The large surface area and high system is about the same as for a can effectively remove chlorine from porosity of activated carbons along reverse osmosis system and feed water. The breakdown of chloramines with material they trap, make them water should be pre-treated prior to by carbon is a relatively slow catalytic a breeding place for microorganisms. going to the membranes. reaction producing ammonia, nitrogen Activated carbon beds need to be and chloride therefore larger volumes periodically sanitised or changed MAJOR PURIFICATION of carbon are needed to handle regularly to minimise bacterial TECHNOLOGIES these. Organic fouling can reduce build-up. the effectiveness of the carbon and is Reverse osmosis (RO) dependent on the local water supply. Water softening (SO) RO membranes are used to remove This should be considered when Hardness in a water supply can result contaminants that are less than sizing its carbon units. in scale formation, which is a deposit 1 nm nominal diameter. Reverse of minerals left over after the water osmosis typically removes 90% to The second application of activated has been removed or evaporated. 99% of ionic contamination, most carbon is in the removal of organic This can be found in reverse osmosis organic contamination, and nearly compounds from potable water. systems, clean steam generators and all particulate contamination from Activated carbon takes up water distillation systems. water. RO removal of non-ionic contaminants by virtue of ionic, polar contaminants with molecular and Van der Waals forces, and by The most common technology weights <100 Dalton can be low. surface-active attraction. Activated used for removing scale formed by It increases at higher molecular carbon beds are prone to releasing calcium and magnesium ions is ion weights and, in theory, removal will fines and soluble components into exchange water softening. A water be complete for molecules with the water stream and do not remove softener has four major components: molecular weights of >300 Dalton all dissolved organic contaminants, a resin tank, resin, a brine tank and and for particles, including colloids but their use can produce a significant valves or controller. When hard and microorganisms. Dissolved gases reduction in TOC. A purer form of water is passed through the resin, are not removed (eg. CO2). activated carbon made from polymer calcium, magnesium, and other beads is sometimes used for this multivalent ions such as iron adheres During reverse osmosis, pretreated application. to the resin, releasing the sodium water is pumped past the input ions until equilibrium is reached. A surface of an RO membrane regeneration is needed to exchange under pressure (typically 4–15 bar, the hardness ions for sodium ions 60–220 psi) in cross-flow fashion. by passing a sodium chloride (NaCl) RO membranes are typically thin solution (called brine) through the film composite (polyamide). They resin. Acidification/Degasification are stable over a wide pH range, can be used as a softening process but can be damaged by oxidising but it has numerous disadvantages, agents such as chlorine, present in such as handling chemical municipal water. Pretreatment of the (sulphuric acid, antiscalant) and feedwater with microporous depth instrumentation for two pH filters, softener and activated carbon adjustments. Nanofiltration is is usually required to protect the sometimes referred to as a softening membrane from large particulates, membrane process and will remove hardness and free chlorine. Typically anions and cations. The feedwater 75%-90% of the feedwater passes requirement for a nanofiltration through the membrane as permeate

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and alkaline solutions. Specially

Feedwater constructed membranes are available for hot water sanitisation at 85°C. Permeate Spiral-wound RO Module Degassing Membrane (DG) A membrane contactor is a Concentrate Permeate hydrophobic membrane device that Product Spacer allows water and a gas to come into direct contact with each other Feedwater RO Membrane without mixing. Water flows on Feed Spacer one side of a membrane and a gas RO Membrane flows on the other. The small pore size and hydrophobic property of Reverse Osmosis membrane schematic of operation the membrane prevents water from passing through the pore. The and the rest exits the membrane as by the addition of recovery RO which membrane acts as a support that concentrate, that contains most of takes the reject and passes it through allows the gas and water to come the salts, organics, and essentially all another RO stage thus reducing the into contact with each other across of the particulates. The ratio of the waste water volume by upto 50%. the pore. By controlling the pressure volume of permeate to the volume and composition of the gas in contact of feedwater is referred to as the Due to its exceptional purifying with the water, a driving force can be “recovery”. Operating an RO system efficiency, reverse osmosis is a very generated to move dissolved gasses with a low recovery will reduce cost-effective technology for the from the water phase into the gas membrane fouling, especially that removal of the great majority of phase. The membrane contactor due to precipitation of low solubility impurities. Reverse osmosis protects works under the same basic salts. However, recoveries of up to the system from colloids and organic principles that vacuum degasifier 90% are possible, depending on fouling. It is often followed by ion or forced draft deaerators operate the quality of the feedwater and exchange or electrodeionisation. under. However, the membrane- the use of filtration and softening Reverse osmosis units need periodic based technology offers a cleaner, pretreatment. cleaning and sanitisation with acid smaller and more stable operating

The performance of the RO component Strip Gas of a water purification system is Distribution Hollow Fiber typically monitored by measuring the Cartridge Tube Membrane Baffle Housing percent ionic rejection, which is the difference between the conductivities of the feed and permeate divided Liquid Liquid Outlet by the feed conductivity, calculated Intlet as a percentage. The ionic rejection and recovery will vary with the Collection Tube feedwater, the inlet pressure, the water temperature and the condition Vaccum Strip Gas of the RO membrane. In the age of sustainability we can further improve Degassing Membrane the water footprint of the RO system 0.03 �m Pore

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of strongly ionic exchange sites. Similarly, negatively charged ions Ions in solution migrate into the (e.g.sulphate, chloride) exchange beads; where, as a function of their with hydroxyl ions on the anion resin. relative charge densities (charge per Anion resin is regenerated using hydrated volume), they compete for strong sodium hydroxide solution the exchange sites. Beads are either (NaOH). cationic or anionic. Strong cation resins are usually polysulfonic acid The very large surface areas of derivatives of polystyrene cross- ion exchange resins makes them linked with divinylbenzene. Strong a potential breeding place for anion resins are benzyltrimethyl microorganisms and can lead to quaternary ammonium hydroxide the release of fines and soluble (Type 1) or benzyldimethlyethyl components. For these reasons, good quaternary ammonium hydroxide quality resins should be used and bed (Type 2) derivatives of polystyrene volumes kept as small as reasonably crosslinked with divinylbenzene. possible. Filters are typically installed system than the conventional after the beds to trap fines and other degasification tower design. The Beds of ion exchange resins are particulate matter. Bacterial build pore size of the membrane is in the available either in cartridges or up can be minimised by frequent order of 0.03 microns, so air-borne cylinders, which are replaced / recirculation of the water and by contamination will not pass through removed from site for remote regular cartridge replacement. the pore and enter the water stream. regeneration, or as an arrangement Membrane degassing is frequently of tanks, vessels, valves and pumps, Modern ion exchange plant design used when treating feed water that which allows on site regeneration of uses relatively small resin beds has a high level of dissolved CO2 (>10- the ion exchange resins. and frequent regeneration – this 15 ppm). Carbon dioxide will freely minimises the opportunity for pass through an RO membrane. As Positively charged ions (e.g. calcium, microbial growth. it passes through an RO membrane magnesium) are removed by the it will dissociate and raise the cation resin by exchanging hydrogen With suitable choice of resin, conductivity of water. Membrane ions for the heavier more highly pretreatment and system design, ion degassing effectively removes the charged cations. Once exhausted exchange enables the lowest levels of dissolved CO2, and maintains a low the cation resin is regenerated by ionic contamination to be achieved. conductivity, which is important exposing the resin to an excess of for subsequent treatment steps, strong acid, usually hydrochloric (HCl). Continuous particularly continuous electro- electrodeionisation(CEDI) deionisation (CEDI). Continuous electrodeionisation is a technology combining ion exchange Ion exchange (IX) resins and ion-selective membranes Beds of ion exchange resins can with direct current to remove ionised efficiently remove ionised species species from water. It was developed from water by exchanging them to overcome the limitations of ion for H+ and OH- ions. Ion exchange exchange resin beds, notably the resins are sub-1 mm porous beads release of ions as the beds exhaust made of highly cross-linked insoluble and the associated need to change or polymers with large numbers regenerate the resins.

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its “clean” non-chemical nature high levels of salts. The small volume and constant high quality water of resins in the stack results in low produced. bleed of organic molecules. Typically, RO removes about 95% of ions; CEDI The resins used in CEDI systems can will remove 99% of the remaining either be separate chambers of anion ions as well as carbon dioxide, or cation beads, layers of each type organics and silica. within a single chamber or an intimate mixture of cation and anion beads. Compared to DI only the combination of RO and CEDI has been the prefered Veolia Water Technologies’ process technology as the RO pharmaceutical CEDI process utilizes provides a very good membrane cation beads in the concentrate barrier for removing bacteria thus stream and layered beds of cation greatly reducing the risk of microbial CEDI Lx Module and anion resins in dilute stream. contamination. CEDI will polish the RO permeate to the required conductivity The resins are housed in wide cells levels required in this market. Reverse osmosis permeate passes that provide a flow path for the ions in through one or more chambers filled transit. This offers advantages in the Typically, CEDI product water has a with ion exchange resins held between flexibility of design and mechanical resistivity of 1 to 18.2 MΩ-cm (at 25°C) cation or anion selective membranes. simplicity on an industrial scale. and a total organic carbon content Ions that become bound to the ion The ion migration from dilute to below 20 ppb. Bacterial levels are exchange resins migrate from the concentrate is enhanced by the minimised because the electrical dilute chamber to a separate chamber layered resin bed in the dilute. conditions within the system inhibit (concentrate) under the influence of the growth of microorganisms. an externally applied electric field, Reverse osmosis (and sometimes which also produces the H+ and OH- membrane degassing) is typically Modern CEDI stacks allow the user necessary to maintain the resins in used before CEDI to ensure that the to carry out hot water sanitisation at their regenerated state. Ions in the CEDI stack is not overloaded with 85°C, for a period of one to four hours. concentrate chamber are recirculated to a break tank or flushed to waste. Feed Water Inlet CONCENTRATE INLET The ion exchange beds in continuous electrodeionisaton (CEDI) systems are regenerated continuously, so they do not exhaust in the manner of ion exchange beds that are operated in batch mode (with chemical regeneration). CEDI beds are typically Anode Cathode also smaller and remain in service for much longer periods.

CEDI is preferred for many purified water generation applications in Pharmaceutical, because of CONCENTRATE OUTLET Dilute Outlet To Service

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reduction in contaminants such as distillate. All distillation units are microorganisms and endotoxins. susceptible to scaling and corrosion. Three designs are available including VC stills require a minimum of water single effect (SE), multi-effect (ME) softening for removing calcium and and vapour compression (VC). In magnesium and also low chlorides a multi effect still, purified steam and silica. ME stills require higher produced in each effect is used feedwater quality; ion exchange or to heat water and generate more reverse osmosis units are usually steam in each subsequent effect. used as pretreatment. Stills are Efficiency increases with each effect sensitive to chlorine and should be Distillation added. In a vapour compression still, protected with activated carbon or The pharmaceutical still chemically steam generated by the evaporation sodium metabisulfite dosing. and microbiologically purifies water of feedwater is compressed and by phase change and entrainment subsequently condensed to form Microporous Filters separation. In this process, water is Microporous filters provide a physical evaporated producing steam. The barrier to the passage of particles steam disengages from the water and microorganisms in purified leaving behind dissolved solids, water systems. Cartridge filters, non-volatiles, and high molecular characterised by absolute particle weight impurities. However, low size ratings, have uniform molecular molecular weight impurities are structures, which, like a sieve, retain carried with water mist/droplets, all particles larger than the controlled which are entrained in steam. A pore size on their surface. separator removes fine mist and entrained impurities, including Cartridge filters (0.05 to 0.22 μm) endotoxins. The purified steam is are typically used before the purified condensed into Water for Injection. water distribution tank to trap Distillation systems are available microorganisms and fine particulates. to provide a minimum of 3 log10 Trapped particulates, including microorganisms or their metabolic products, and soluble matter, can Distillation - The Philosophy be leached from filters and suitable maintenance (regular sanitisation Inclined condenser and periodic replacement) is necessary to maintain desired levels Vent Steam of performance. Newly installed filters Condense usually require rinsing before use to Separator of WFI quality remove extractable contaminants. Boiling Steam & chamber Water droplets A microporous filter membrane

Water inlet is generally considered to be Heat source indispensable in a water purification system, unless it is replaced by an ultraviolet generator or ultrafilter.

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Ultrafilter TECHNOLOGIES USED TO CONTROL MICROORGANISMS

Ultrafiltration (UF) is a cross- MICROPOROUS ULTRA REVERSE ULTRA-VIOLET flow process similar to reverse FILTER FILTER OSMOSIS LIGHT osmosis. The membrane rejects MICROORGANISMS     particulates, organics, microbes, pyrogens and other contaminants ENDOTOXINS     that are too large to pass through Key:  Excellent removal,  Good removal,  Partial removal. the membrane. UF has a stream to waste (concentrate) that can be recirculated. In polishing applications, this is generally 5% of the feed flow. 0.25 EU/ml. UF membranes can be test they also pass a challenge test Membranes are available in both sanitised with a variety of chemical with live bacteria – in other words, polymeric and ceramic materials. The agents such as sodium hypochlorite, the filters are working correctly. former is available in spiral wound hydrogen peroxide, peracetic acid The different integrity test methods and hollow fibre configurations and and with hot water and / or steam. the ceramic membranes are available 1. Bubble point in single and multiple channel Vent filters The pressure at which liquid is configurations. Ultrafiltration Hydrophobic microporous filters ejected from the largest pores thus is frequently used downstream are often fitted to water storage allowing mass flow of gas. of ion exchange deioniser or containers as vent filters in order 2. Pressure decay reverse osmosis/ continuous to prevent particulates, including electrodeionisation processes for bacteria, from entering the stored The most commonly adopted microbial and endotoxin reduction. water. Regular replacement is method with wide acceptance. The rating of UF membranes varies in essential to maintain effectiveness. 3. Diffusional flow molecular weight cut-offs from 1 ,000 to 100,000 and UF has reduction of Why integrity test vent filters? Uses the same principles and is endotoxin (pyrogens) from 2 log10 to To assure filter performance prior to closely related to pressure decay. 4 log10. UF is capable of consistent use: 4. Water intrusion test (WIT) production of water meeting the � To meet regulatory requirements USP/Ph Eur WFI endotoxin limit of ► FDA Only used to test hydrophobic PTFE ► cGMP guidelines to achieve best membrane filters used for gas practices sterilisation. ► Prevention of batch loss/ reprocessing

What is an integrity test? � A non-destructive test that directly correlates to a destructive bacterial challenge test

Integrity testing � By proving the link between bacterial challenge testing and integrity testing, the user can be sure that if filters pass an integrity

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feedwater to remove particulates, Germicidal lamp output verses germicidal effectiveness chlorine or chloramines, calcium

Germicidal Lamp and magnesium. This is preferably 100 Output at 253.7 nm followed by reverse osmosis to 90 remove virtually all colloids, particles 80 Germicidal Effectiveness and high molecular weight organic 70 Curve with Peak at 265 nm compounds and over 90% of ions. 60 The resultant deionised water will 50 185 nm Output Line contain some organic compounds, 40 Other Germicidal Lamp some ions, some bacteria and cell 30 Output Lines debris and all the dissolved carbon 20 Relative output or effectiveness Relative dioxide and oxygen. 10 0 The water is next treated by one 180 210 240 270 300 330 360 390 420 Wavelength in Nanometers (nm) or more techniques depending on the required purity - ion exchange or second stage reverse osmosis Ultraviolet light continuous electrodeionisation. or CEDI to remove ions, UV light Ultraviolet light is used as a 185nm UV is also used to destroy to kill bacteria and/or to oxidise bactericide and to break down and excess chlorine or ozone. UV residual organic compounds and photo-oxidise organic contaminants radiation at 185nm is a highly ultrafiltration to remove endotoxin, to polar or ionised species for effective photo-oxidant and a key protease and nuclease. Any or all of subsequent removal by ion exchange. component in producing purified these stages can be combined in the water with the lowest levels of same unit as the reverse osmosis or The UV sources in pharmaceutical organic contaminants. separately in a polisher. water purification systems are low or medium pressure mercury vapour System design Storage tanks and distribution are lamps. Radiation with a wavelength The different technologies described potential sources of contamination, of 240-260nm has the greatest on the previous pages can be combined particularly from bacteria. Good bactericidal action with a peak at in a variety of ways to achieve the design and proper maintenance 265nm. It damages DNA and RNA desired degree of water purification. regimes are needed to minimise polymerase at low doses preventing problems. The choice of materials of replication. For most pharmaceutical Each system will require some construction is also critical. Metals, applications, UV chambers and pretreatment based on the particular other than stainless steel, should lamps need to be designed to provide a sufficient dosage of UV to achieve a 6 log10 reduction of typical pathogenic contaminants.

Radiation at shorter wavelengths (185nm) is effective for the oxidation of organics. The UV breaks large organic molecules into smaller ionised components, which can then be removed by downstream

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be avoided. There are many high purity plastics available but care needs to be taken to avoid those with fillers and additives which could contaminate the water. Storage tanks should be protected from ingress of contaminants with suitable vent filters. The purified water is recirculated continuously and cooled down to maintain purity. UV disinfection is often used to maintain microbial purity in the distribution loop. Continuous ozonation of the storage tank can also provide greater regimes, protocols and guidelines � Volume 5 – Commissioning and microbial control. laid out by the regulatory authorities Qualification and the industry bodies, typically: � Volume 8 – Maintenance Validation and trend The water standards in the monitoring pharmacopoeias US regulation 21CFR11 Electronic Process validation is defined as � USP – United States Pharmacopoeia records and electronic signatures “establishing documented evidence � Ph Eur – European Pharmacopoeia which provides a high degree of � JP – Japanese Pharmacopoeia ‘GAMP 5’ – a guideline for the assurance that a specific process will ‘Good Manufacturing Practice’ validation of automated systems consistently produce a product (GMP) meeting its predetermined � FDA Code of Federal Regulations ISO 9001 – Quality Management specifications and quality attributes”1. 21CFR210 and 21CFR211 System approval � The Rules Governing Medicinal Validation is the process of Products in the European Union The documents created for a validated documenting the design, installation, Volume 4 water treatment system may vary operation and performance of an from site to site; however, the operating system. Periodically all water ISPE ‘Baseline® Guide’ standard documents are generally treatment systems may be inspected � Volume 4 – Water and Steam covered in the following list of by the local or international inspecting Systems documents. authorities to ensure that the pharmaceutical facility complies with the local or international regulations. Ultimately the user is responsible for validating the water system to make sure that it meets the requirements of the inspectors; however, the supplier will need to provide most of the test documentation for the water treatment plant.

The validation documentation package should follow the various

1 Guidelines on general principles of 14 process validation - FDA May 1987. PHARMACEUTICAL PURE WATER GUIDE

DOCUMENTATION LIST

ABBREVIATION / DOCUMENT FULL TITLE WHAT IT IS FOR

To tell the supplier what the customer requires, what specification that needs to be adhered to, how much water is URS User Requirement Specification needed, what the water system is to do, etc. Document created by the client or his engineer.

This documents the client’s approach to validation on site and in particular to the current site project. It identifies the scope VMP Validation Master Plan of the validation exercise allowing the validation on site to be suitably managed. Created by the client or his engineer.

This document defines how the supplier will fulfil the user and supplier’s quality requirements on the project. It also provides details of the project management on the contract. This may QPP Quality & Project Plan include a Gantt chart for the project management of the contract. This is the supplier’s response to the VMP. Document created by the supplier.

This document gives details of how and when the equipment that is to be supplied is inspected at the supplier’s works. QIP Quality Inspection Plan This details the type of inspection and who will inspectthe equipment. It also gives options and suggests when the client inspects it. The document is created by the supplier.

To describe the components of the equipment, how it will be FDS Functional Design Specification connected and how the system functions. This is the supplier’s response to the client’s URS. Document created by the supplier.

Drawing of the system, that shows all valves, instruments, and P&ID Process and Instrument Diagram equipment. This is the principal design document created by the supplier.

Lists all the valves and the valve specification. Created by the VALVE SCHEDULE Valve Schedule supplier.

Lists all the instruments and the instrument specification. INSTRUMENT SCHEDULE Instrument Schedule Created by the supplier.

Lists all the equipment and the equipment specification. EQUIPMENT SCHEDULE Equipment Schedule Created by the supplier.

Lists all the utilities and the utility specification, such as water, UTILITIES SCHEDULE Utilities Schedule drains, electricity, steam, air, chemicals, etc. Created by the supplier.

Equipment layout drawing, showing information as to the GA DRAWING General Arrangement Drawing connection of the equipment and its location.

The design qualification or enhanced design review is carried out to ensure that the designed equipment, using the design DQ Design Qualification documents, meets the user requirements. The review is documented and created by the supplier.

SDS Software Design Specification To describe the control panel software function and design.

STS Software Test Specification To test the functions described in the SDS.

HDS Hardware Design Specification To describe the control panel hardware function and design.

HTS Hardware Test Specification To test the functions described in the HDS.

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DOCUMENTATION LIST

ABBREVIATION / DOCUMENT FULL TITLE WHAT IT IS FOR

To categorise configurable instruments. This gives information Good Automated Manufacturing Practice GAMP CATEGORISATION on how to record configuration and validation processes that Categorisation should be used.

To test the equipment at the supplier’s factory without running water through the system. The system does not have to be MFAT Mechanical Factory Acceptance Test fully assembled for this. Checks include ensuring the correct equipment is available.

To test the equipments operationally in the factory with water. FAT Factory Acceptance Test This tests all the equipment's functionality.

This document tests the equipment on site. The SAT can be a combination of the IQ, Commissioning and OQ documents, SAT Site Acceptance Test depending on each client’s understanding. The supplier creates the SAT document.

To document that the equipment is correctly installed on site IQ Installation Qualification as intended. The supplier normally creates this document.

To document that the system is correctly set up and that the system is made ready for full functional operation. This COMMISSIONING PROTOCOL Commissioning document records all the start up data. The supplier creates this document.

To document that the system functions and operates as OQ Operation Qualification described in the FDS. The supplier normally creates this document.

To record that the system produces good quality water and PQ Performance Qualification that the quality is consistent when the system is online. The user creates this document.

Change Control is the most variable component of a water system is carried out on a Key to the validation effort is the a water system and so regular and regular basis, determined by the control and evaluation of change detailed monitoring is required. monitoring of bacteria in the system. both during the time scale of the This monitoring will aid the The method used for sanitisation project and in subsequent ongoing determination of when the system depends on a number of factors use. Inspectors mandate change should be sanitised. such as the materials of construction control for processes, equipment and the design intent. If the system and control systems. The aim of Sanitisation is made of plastic materials then any change control is to provide an Sanitisation of the water purification a chemical sanitisation method is auditable trail and to ensure a state and distribution system is critical to used, as most plastics cannot accept of control. ensure that microbial contamination high temperatures. Per-acetic acid is controlled within specifications. and hydrogen peroxide are often Performance Sanitisation frequency must be used as chemical sanitants. Where The ongoing performance of the adequate to maintain the purity the materials of construction are plant is monitored regularly by specifications and is established metal or plastics suitable for high the user. The user needs to be in based on system usage, regular temperature then heat is frequently control of the quality of water quality control trend data, and used. Hot water (85°C), overheated produced by the system. Typically the system manufacturer’s water (121°C), steam or ozone are the bacteria content of the water recommendation. Sanitisation of frequently used for sanitisation.

16 PHARMACEUTICAL PURE WATER GUIDE

PURIFIED WATER

Veolia Water Technologies content of less than 500 ppb and a differentiates between two kind of bacterial count below 100 CFU/ml. applications of process water used in Water of this quality can be used for a the pharmaceutical industry: multiplicity of applications, including make up and rinse water for large and Non-Critical utilities and Critical small volume parenterals, genetically utilities engineered drugs, serum/media, ophthalmic solutions, antibiotics, Non-Critical utilities vaccines, cosmetics, veterinary These are non-validated systems products, OTC and ethical products, for applications such as boiler feed, fermentation, medical devices, cooling tower make up, feed to nutraceuticals and diagnostics. large glass washers and autoclaves. Purified water can be produced Reverse osmosis and Ion exchange by water purification systems are the most commonly used water incorporating reverse osmosis and ion treatment technologies in non-critical exchange, second pass RO or CEDI, utilities. and often also with UV treatment.

Critical utilities Purified apyrogenic water is required Purified water not only has relatively in applications such as mammalian high purity in ionic terms, but also low cell culture. Ultrafiltration is used concentrations of organic compounds to remove any significant levels of and microorganisms. A typical biologically active species such as specification would be a conductivity endotoxin (typically <0.25 IU/ml) of <1.0 μS/cm (resistivity >1.0 MΩ- and nucleases and proteases (not cm), a total organic carbon (TOC) detectable).

17 PHARMACEUTICAL PURE WATER GUIDE

WATER FOR INJECTION - WFI

Water for Injection (WFI) is used as Clean steam an excipient in the production of Clean steam or Pure steam, as it is parenteral and other preparations sometimes known, is used where where product endotoxin content the steam or its condensate would must be controlled, and in other directly contact official articles or pharmaceutical applications, such as article-contact surfaces, such as the cleaning of certain equipment during their preparation, sterilisation, and parenteral product components. or cleaning where no subsequent processing step is used to remove The minimal quality of source any impurity residues. These clean water for the production of WFI is steam applications include, but are drinking water whose attributes are not limited to, porous load sterilisation prescribed by the U.S., EPA, EU, Japan, processes, product or cleaning solution or the WHO. This source water may heated by direct steam injection, or be treated to render it suitable for humidification of processes where subsequent final purification steps, steam injection is used to control the such as distillation (or whatever humidity inside processing vessels other validated process is used where the official articles or there according to the monograph). in process forms are exposed. The The finished water must meet primary intent of using this quality all of the chemical requirements of steam is to ensure that the official specified in the monograph, as article or article-contact surfaces well as an additional bacterial exposed to it are not contaminated by endotoxin specification. Because residues within the steam. endotoxins are produced by the kind of microorganisms that are Clean steam can be qualitatively prone to inhabit water systems, the described as steam that meets equipment and procedures used all the requirements of WFI, after by the system to purify , store and condensation. There are no physical distribute WFI should be designed tests for limits on non-condensable to control microbial contamination gasses or percentage saturation. The and must be designed to remove USP monograph specifically notes incoming endotoxins from the source the physical requirements are not water. WFI systems must be validated stated, but adds: “the level of steam to reliably and consistently produce saturation or dryness, and the amount and distribute this quality of water. of non-condensable gases are to be determined by the Pure Steam application.”2 This puts the burden on the user to determine appropriate physical properties depending on the use of the steam.

2 USP monogram. 18 PHARMACEUTICAL PURE WATER GUIDE

MONITORING THE PURITY OF PURIFIED WATER

It is impractical to monitor all VARIATIONS OF RESISTIVITY WITH TEMPERATURE potential impurities in purified TEMPERATURE RESISTIVITY OF PURE WATER RESISTIVITY OF water. Different approaches are used (°C) (MΩ-cm) 20.7 ng/g NaCl in water (MΩ-cm) for different types of impurities. 0 86.19 28.21

The key rapid, on-line techniques 5 60.48 22.66 commonly used are resistivity and 10 43.43 18.30 TOC measurement. 15 31.87 14.87 Conductivity/Resistivity 20 23.85 12.15 25 18.18 10.00 The chemical attributes of purified Water and Water for Injection (WFI) 30 14.09 8.28 were in effect prior to USP23 were 35 11.09 6.90 specified by a series of chemistry 40 8.85 5.79 tests for various specific and non 45 7.15 4.89 specific attributes with the intent of 50 5.85 4.15 detecting chemical species indicative of incomplete or inadequate purification. Although these methods that primarily targeted organic could have been considered barely contaminants. A multi-staged adequate to control the quality of conductivity test that detects ionics these waters, they nevertheless (mostly inorganic) contaminants stood the test of time. This was replaced, with the exception of the partly because the operation of water tests for heavy metals, all of the systems was, and still is, based on on- inorganic chemical tests. line conductivity measurements and specifications generally thought to preclude the failure of these archaic chemistry attribute tests.

In 1996, USP moved away from these chemical attribute tests, switching to contemporary analytical technologies for the bulk waters purified water and Water for Injection. The intent was to upgrade the analytical technologies without tightening the quality requirements. The two contemporary analytical technologies employed TOC and conductivity. The TOC test replaced the test for oxidisable substances

19 PHARMACEUTICAL PURE WATER GUIDE

Total (TOC) levels <25 ppb and recommended at Due to the potential variety and <50 ppb. complexity of organic compounds present in purified water it is not The main role of TOC is for monitoring practical to measure them all and trending. In most waters TOC routinely. An indicator of overall cannot be related directly to the organic contamination is needed. The concentration of organic molecules most useful has proved to be TOC. in the water as the amount of carbon Organic substances in a water sample is different in different molecules. For are the resultant oxidation products example, 100 ng/g (ppb) of carbon is detected. A wide range of TOC present in a solution of 131 ng/g (ppb) analyzers exist and can be broadly phenol or 990 ng/g (ppb) chloroform, divided into those which oxidise all because phenol contains 76% by the carbon to carbon dioxide and weight of carbon and chloroform measure the CO2 selectively and contains 10% by weight of carbon. those that either partially oxidise the organic compounds, to acids The requirements for TOC monitoring for example. Others fully oxidise all are a very rapid response and species present and measure the continuous availability, with change in conductivity due to all the sufficient sensitivity and precision. oxidised species. The latter reading will include, for example, nitric and TYPICAL VALUES OF TOC PPB sulphuric acids from the oxidation of µS/cm

N and S atoms. The former are usually Mains water 500 - 5000* used off-line to show compliance RO permeate 25 – 100 with TOC specifications. The latter DI water 50 – 500 are used for in-line monitoring. Due RO + CEDI 5 – 30 to the risks of contamination, in-line measurements are essential for TOC * (typically 1000 – 3000)

20 PHARMACEUTICAL PURE WATER GUIDE

WATER PURITY STANDARDS

Purified water is used in most PHARMACOPOEIA REQUIREMENTS FOR PURIFIED WATER pharmaceutical manufacturing PROPERTIES Ph Eur USP processes all around the world. CONDUCTIVITY <4.3 µS/cm at 20°C <1.3 µS/cm at 25°C* Therefore, international and national TOC <500 µg/l C** <500 ppb authorities have established water BACTERIA (guideline) <100 CFU/ml <100 CFU/ml quality standards for purified and NITRATES <0.2 ppm - other regulated grades of water. Key authorities include: HEAVY METALS <0.1 ppm -

� The United States Pharmacopoeia TEMPERATURE/CONDUCTIVITY REQUIREMENTS (FOR PH EUR) (USP) (for non-temperature compensated conductivity measurements) � The European Pharmacopoeia (Ph Eur) TEMPERATURE °C CONDUCTIVITY µS/cm � The Japanese Pharmacopoeia (JP) 0 2.4 10 3.6

20 4.3 The standards in this section are a 25 5.1 summary and correct at the time of going to press3. Standards are 30 5.4 regularly reviewed and updated 40 6.5 and users should refer to the latest 50 8.1 version of the full standards. 60 9.1 70 9.7

Pharmacopoeia standards 80 9.7

Separate pharmacopoeia are 90 9.7 produced by a number of authorities, 100 10.3 notably in the USA, Europe and Japan. Each specifies materials, including water, to be used in pharmaceutical PHARMACOPOEIA REQUIREMENTS FOR WATER FOR INJECTION AND HIGHLY work. The standards for purified PURIFIED WATER water are similar in each case. Extra PROPERTIES Ph Eur USP criteria are set for water required for CONDUCTIVITY <1.1 µS/cm at 20°C*** <1.3 µS/cm at 25°C* sterile applications. The standards for TOC <500 µg/l C** <500 ppb purified water given in the European BACTERIA (guideline) <10 CFU/100ml <10 CFU/100ml Pharmacopoeia (Ph Eur) and in the ENDOTOXINS <0.25 IU/ml <0.25 EU/ml United States Pharmacopoeia (USP) are summarized below. Water for NITRATES <0.2 ppm - injection has stringent bacterial/ HEAVY METALS <0.1 ppm - pyrogen criteria and methods of * Offline conductivity measurements possible. If in-line conductivity exceeds values then refer to USP preparation are specified. tables in section 645 (Table 1). If value exceeds that in table 1, refer to Three Stage Philosophy. ** Or pass oxidisable substances test.

*** If in-line conductivity exceeds values then refer to the European Pharmacopoeia (Ph Eur).

3 as of going to print 2020. 21 PHARMACEUTICAL PURE WATER GUIDE

Three Stage Philosophy As well as defining the absolute USP and JP allow the use of other Stage 1 water quality standards, the technologies, such as reverse osmosis � Temperature not less than 25°C pharmacopoeia monographs give and ultrafiltration, for the production and conductivity not greater than guidance on appropriate treatment of WFI. Since April 2017 EP has 1.3 μS/cm processes for producing the various fallen in line and will accept a twin � SAMPLE PASSES TEST types of regulated water. These membrane system for cold WFI water are generally non-prescriptive. production. If measured on-line the conductivity meter must be calibrated and non temperature compensated, the temperature must be measured TABLE 1 TABLE 2 independently by an adjacently STAGE 1: TEMPERATURE/CONDUCTIVITY STAGE 3: CONDUCTIVITY installed calibrated temperature meter. REQUIREMENTS (FOR USP) REQUIREMENTS (FOR USP) If the temperature is less than 25°C or (for non-temperature compensated AS A FUNCTION OF PH conductivity measurements) the conductivity greater than 1.3 μS/cm then the conductivity measured must TEMPERATURE °C CONDUCTIVITY µS/cm pH µS/cm be checked against the Temperature/ 0 0.6 5.0 4.7 Conductivity chart table 1. 5 0.8 5.1 4.1 10 0.9 5.2 3.6

Stage 2 15 1.0 5.3 3.3

� The temperature adjusted to 25°C 20 1.1 5.4 3.0

when change in conductivity 25 1.3 5.5 2.8

is less than a net 0.1 μS/cm per 30 1.4 5.6 2.6 five minutes take a conductivity 35 1.5 5.7 2.5 reading: 40 1.7 5.8 2.4 � If it is not greater than 2.1 μS/cm 45 1.8 5.9 2.4 then it meets the requirements 50 1.9 6.0 2.4 � If it is greater than 2.1 μS/cm then go to stage 3 55 2.1 6.1 2.4 60 2.2 6.2 2.5 Stage 3 65 2.4 6.3 2.4 � Temperature at 25°C 70 2.5 6.4 2.3 � Determine pH 75 2.7 6.5 2.2

80 2.7 6.6 2.1

If conductivity reading in stage 2 85 2.7 6.7 2.6 is not greater than conductivity 90 2.7 6.8 3.1 reference for given pH (table 2) it 95 2.9 6.9 3.8 meets the requirements. If the pH is 100 3.1 7.0 4.6 outside the range 5.0 – 7.0 the water does not meet requirements.

22 PHARMACEUTICAL PURE WATER GUIDE

MAINTENANCE OF THE WATER PURIFICATION SYSTEM

In order to ensure that once qualified, contracts. These types of maintenance the facility remains in a state of contracts focus on maintaining the qualification, a preventative system in a state as close to that at maintenance programme must be which it operated at commissioning. developed. In order to enable this All parameters are recorded during programme to be established, the contract visit and adjusted detailed operating and maintenance accordingly with all changes recorded. instructions, together with Cleaning, repairs and preventative monitoring log sheets and spares maintenance operations are recorded lists, need to be provided. The within the report sheets. The final specialist water treatment supplier report will also give details of any can typically provide maintenance recommended and necessary actions.

23 PHARMACEUTICAL PURE WATER GUIDE

PURIFIED WATER APPLICATIONS

Buffer and media preparation direct steam heating, injection and provides the CIP make up and rinse The grade of pure water required in autoclaves and sterilisers. Most water. Different water types are for reagent make-up or dilution steam generators benefit from used to suit different manufacturing will depend on the sensitivity of pretreatment of the water supply processes. Purified water is most the intended application. For many to avoid build-up or precipitation commonly used. general pharmaceutical applications of contaminants and so reduce where sensitivity is not the primary maintenance, improve performance Microbiological Analysis factor, purified water is sufficiently and enhance hygiene levels. Steam Routine microbiological analysis pure. It has the added advantage of generators can use purified water requires purified water. This not only having high purity in ionic with conductivity of <1 μS/cm (> will be largely free of bacterial terms, but, by also incorporating UV 1.0 MΩ-cm resistivity). It is typically contamination and have low levels and filtration, can also ensure low produced by reverse osmosis coupled of ionic, organic and particulate levels of organic contaminants and with electrodeionisation after impurities. Typical values are a microorganisms. suitable pretreatment. resistivity of <1 μS/cm, TOC <50 ppb and <100 CFU/ml bacteria count. Feed to Ultra-pure water Glassware washing or rinsing systems Glassware washing is an everyday Qualitative Analysis The production of ultra-pure water practice in most Pharmaceutical The water required for most (18.2 Mohm-cm resistivity, <5ppb laboratories and the grade of water qualitative analysis methods for TOC) from tap water or its equivalent required for the task will depend major or minor constituents is is usually carried out in two stages: on the nature of the intended general grade purified water with pretreatment and polishing. Ideally, application. To minimise costs, most resistivity <1 μS/cm, TOC less than pretreatment reduces all the major general-purpose glassware can be 50 ppb and low particulates and types of impurities - inorganic, washed with purified water. bacterial counts. organic, microbiological and For more sensitive analytical or particulate - by over 95%. This can genetic techniques, Water for Water analysis be achieved most effectively using Injection or highly purified water Water analyses are carried out reverse osmosis or reverse osmosis grade can be used. Conductivity for many different reasons. combined with CEDI. should be <0.05 μS/cm, TOC less Requirements include ensuring than 10 ppb and bacterial counts potable water meets current Feed to stills <10 CFU/100ml. standards, checking purification A long-established method for water processes have been successfully purification, distillation is most Cleaning in place carried out and environmental effectively performed with pretreated Cleaning in place (CIP) is an testing of feed sources such as water to minimise the build up of everyday practice in pharmaceutical lakes and rivers. Water analysis precipitates and the carry over of manufacturing. CIP involves requires purified water for the impurities. It is common practice periodically cleaning reactors, pumps, preparation of samples, standards to feed a still with purified water, heat exchangers, distribution loops and blanks. This water must be of particularly where multi-effect stills and process filling machines. Some a known purity that is sufficiently are used. processes are cleaned between high so as not to interfere with the each batch. The sporadic nature of analytical techniques. Water analysis Pure Steam Generators (PSG) CIP means that demand flow rate applications are usually performed Steam generators are used in a range can vary widely, and this has to be with water with resistivity of of applications including clean room factored into the design of the water <0.2 μS/cm, TOC <50 ppb and a humidification, moisturisation, generation and storage system that bacterial count below 1 CFU/ml.

24 PHARMACEUTICAL PURE WATER GUIDE

APPLICATIONS AT A GLANCE Analytical and General Applications

CONDUCTIVITY TOC FILTER BACTERIA ENDOTOXIN GRADE OF TECHNIQUE SENSITIVITY μS/cm ppb μm CFU/ml IU/ml PURE WATER

Buffer and media General <1 <500 NA <100 NA Purified water preparation

Feed to stills Low <1 <500 NA <100 NA Purified water

Feed to Ultra-pure General <1 <50 NA <1 NA WFI HPW water systems

General <1 <50 <0.2 <10 NA Purified water Glassware washing High <0.05 <10 <0.2 <1 NA WFI HPW

General <1 <50 NA <100 NA Purified water Cleaning in place High <0.05 <10 NA <0.1 <0.25 WFI HPW

Microbiological General <1 <50 <0.2 <100 NA Purified water analysis

Qualitative Analysis General <1 <50 <0.2 <1 NA WFI HPW

Steam generation General <1 <500 NA <100 NA Purified water

General <0.2 <50 <0.2 <1 NA Purified water High <0.05 <10 <0.2 <0.1 <0.25 WFI HPW

Critical impurities - NA Not applicable

25 PHARMACEUTICAL PURE WATER GUIDE

PURE WATER - HINTS & TIPS

1 Stored purified water must be 6 Appropriate pipework, fittings 11 CEDI technology modules must continuously recirculated and quality and finishing must be be fed with reverse osmosis the equipment periodically used in order to avoid dead–legs, quality water. Hardness, sanitised. crevices, etc. particules, organics, oxidising agents, iron and manganese 2 Temperature should be actively 7 The 0.22μm cartridge filter and must be removed before the controlled in the system by vent filter should be changed module. means of either heating or regularly; typically at least cooling heat exchangers, or every six months, to minimise 12 For chemical or hot water by periodic purging to avoid the build–up of bacterial sanitization of the CEDI module, overheating. contamination. the module must be able to bear chemical agents, such as 3 The microbiological purity of 8 At least 5 to 10 minutes of purified peracetic acid and hydrogen the water in a water treatment water should be run to drain peroxide or hot water at >85°C system can only be maintained after a period of inactivity, e.g. for a minimum of one hour. This by recirculating the water before feeding the purified water should be checked before initial through the various purification tank or during the weekend. sanitisation. processes via the break tank. The break tank should be of sanitary 9 To ensure efficient operation of 13 For pretreatment UV, design and construction. the resistivity meter, a qualified proper pre-filtration should individual should clean the be implemented to keep 4 Regular sanitisation is essential electrodes of the line cell and particulate from shielding to prevent build–up of calibrate the resistivity meter organisms from UV light. biofilm. Heat is the preferred every 12 months. sanitisation method although 14 UV lamps should be replaced at hydrogen peroxide and ozone 10 To prolong the life of a reverse appropriate intervals (4,000– can also be effective. Ozone osmosis membrane, it should be 10,000 hours depending on and hot water sanitisation are regularly flushed and cleaned. type) and the quartz thimble/ suitable for the storage and Flushing removes particulate sleeve should be cleaned at the distribution loop. matter or precipitated solids same time. from the membrane surface. 5 To prevent algal growth, use of translucent tanks and pipework should be avoided and storage vessels should not be installed close to direct sunlight or sources of heat.

26 PHARMACEUTICAL PURE WATER GUIDE

GLOSSARY OF TERMS

Absorption – A process by which a Calibration – A comparison of a Concentrate – The liquid containing substance is taken up chemically measurement instrument to detect, dissolved and suspended matter that or physically in bulk by a material correlate or eliminate by adjustment concentrates on the inlet side of a (absorbent) and held in pores or of any variation. membrane and flows to drain. interstices in the interior. Carbon fines – Very small particles Condenser – The stage of a Activated carbon – A highly porous of carbon that may wash out of an distillation system that removes form of carbon used for sorption of activated carbon bed. sufficient heat from a vapourised organics and removal of free chlorine liquid to cause the vapour to change and chloramine. Cartridge – A pre–packed disposable to a liquid phase. container for housing a water Adsorption – Adherence of molecules, purification media or membrane. Conductivity – Conductivity is the atoms and ionised species of gas reciprocal of resistivity. For water or liquid to the surface of another Cation exchange resin – An ion purification systems, conductivity is substance (solid or liquid) as the result exchange resin with immobilised usually reported as microsiemens per of a variety of weak attractions. negatively charged exchange sites, centimeter (μS/cm). which can bind positively charged Anion exchange resin – An ion ionised species, cations. Contactor membrane (DG) – exchange resin with immobilised A hydrophobic membrane used in positively charged exchange sites, CFU/ml – Colony Forming Units removing dissolved gases (CO2 or O2) which can bind negatively charged per milliliter. A measure of viable from water. ionised species, anions. microbial populations. Continuous Electrodeionization Azeotrope – A blend of two or more Channeling – Preferential flow of (CEDI) – Technology combining ion components with equilibrium vapour water through a resin/granular exchange resins and ion selective phase and liquid phase compositions activated carbon bed effectively membranes with direct current to that are the same at a given causing bypass of ion exchange/ remove impurity ionised species from temperature and pressure. activated carbon sites. Poor quality water without regeneration phase. and capacity will result. Backwash – The upward flow of water Deadleg/Dead Volume – A region or through a resin or carbon bed to clean cGMP – Current Good Manufacturing volume of stagnation in an apparatus it, and in the case of a mixed bed, to Practice. or distribution system. separate anion and cation resins.

Colloid – A stable dispersion of De-gassing – The removal of O2 and

Bactericide – A chemical or physical fine particles in water that have a CO2 from water, usually by transfer agent that kills bacteria. typical size less than 0.1 μm. Colloids across a hydrophobic membrane.

containing iron, aluminium, silica CO2 is removed to increase ion Biocide – A chemical or physical and organics are commonly found in exchange capacity and improve agent that kills microorganisms. natural and potable waters. electrodeionisation efficiency.

Biofilm – A layer of microorganisms Color change resin – A resin that is Deionisation (DI) – Removal of enclosed in a glycoprotein dyed with a pH indicator so that it impurity ions from water. Usually polysaccharide matrix which are changes color upon exhaustion to used to refer to ion exchange – see adherent to each other and/or to indicate when the cartridge needs ion exchange. surfaces. replacing.

27 PHARMACEUTICAL PURE WATER GUIDE

Deionisation service – see service GAMP – Good Automated Line Cell – An electrode assembly deionisation. Manufacturing Practice. inserted into a water stream by which the conductivity or resistivity Distillation – A purification process Gram-negative – refers to bacteria is measured. that takes advantage of changing that do not absorb a violet stain the phase of a substance from liquid originally described by Gram. Microorganism – Any organism to vapour and back to liquid usually that is too small to be viewed by at the boiling temperature of the Gram-positive – Refers to bacteria the unaided eye, such as bacteria, substance, in order to separate it that absorb a violet stain originally viruses, molds, yeast, protozoa, and from other substances with higher or described by Gram. some fungi and algae. lower boiling points. Hardness – The scale–forming Nuclear grade resin – A high purity Endotoxin – A thermally stable and lather–inhibiting qualities of (analytical) grade of ion exchange lipopolysaccharide component from some water supplies, caused by resin originally developed for the the cell wall of viable or nonviable high concentrations of calcium nuclear energy industry. Gram–negative microorganisms. Can and magnesium. Temporary act as a pyrogen. hardness, caused by the presence of Offline – In water monitoring magnesium or calcium bicarbonate, systems, referring to measurement Endotoxin Units (IU/ml or EU/ is so called because it may be devices that are not directly coupled ml) – A quantification of endotoxin removed by boiling the water to to the water stream. levels relative to a specific quantity convert the bicarbonates to the of reference endotoxin. 1 IU/ml is insoluble carbonates. Calcium and Online – In water monitoring approximately equal to 0.1 ng/ml. magnesium sulfates and chlorides systems, referring to measurement cause permanent hardness. devices directly coupled to the water Exotoxin – A toxic substance stream. secreted by a bacterium, often HPW – Highly purified water. causing disease, which can also act Oxidation – A process using as a pyrogen. Ion – Any non–aggregated particle short wavelength light to kill of less than colloidal size possessing microorganisms and cleave or oxidise FDA – United States Food and Drug either a positive or a negative electric organic molecules. Administration. charge. Ozone – Ozone is used in the Feedwater – The water that is Ion exchange (IX) – The process of pharmaceutical industry as a introduced into a purification process. purifying water by removing ionised sanitising agent. O3 is a very strong salts from solution, by replacing oxidising agent that kills bacteria Filtration – A purification process in hydrogen ions for cation impurities and reduces TOC in water. which the passage of fluid through and hydroxyl ions for anion a porous material results in the impurities. Particulates – Discrete quantities of removal of impurities. solid matter dispersed in water. LAL – Limulus Amoebocyte Lysate, Fines – Particulates released from a an extract from the horseshoe crab Permeate – The purified solution bed of material such as ion exchange which forms a gel in the presence which has been produced by passage resins. of sufficient endotoxin. Used as the through a semi–permeable reverse basis for the LAL test for endotoxins. osmosis membrane. Fouling Index – see Silt Density Index.

28 PHARMACEUTICAL PURE WATER GUIDE

pH – A measure of the acidity or Qualification – The act of establishing SJP (JP) – The Society of Japanese alkalinity of a solution equal to –log with documented evidence that the Pharmacopoeia (SJP) is a non– (H+). process, equipment, and/or materials profit foundation authorised by are designed, installed, operated the Ministry of Health, Labour and PhEur – European Pharmacopoeia. and perform according to the pre– Welfare (MHLW). It was established determined specifications. mainly to promote dissemination Photo–oxidation – see ultra violet of the Japanese Pharmacopoeia (JP) (Photochemical) oxidation. Regeneration – The method by which for the purpose of maintenance exhausted ion exchange resins are and improvement in the efficacy, Planktonic – Used to describe aquatic reactivated by treatment with strong safety and quality of pharmaceutical microorganisms that float. acid or alkali. drugs.

Point of use – A dispense point from Resistivity – The electrical resistance Softening – A water treatment a purified water system from which between opposite faces of a one– process whereby cations, notably water can be taken. centimetre cube of a given material at hardness–forming calcium and a specified temperature. Resistivity is magnesium ions, are exchanged for Polishing – The final treatment stage(s) the reciprocal of conductivity. For water sodium using cation exchange resins of a water purification system. analysis, resistivity is usually reported in the sodium form. in megohm–centimetres (MΩ–cm). Potable water – Water which meets Stagnation – State of a liquid regulations as suitable for ingestion Reverse osmosis (RO) – A process in without current or circulation. by humans. which water is forced under pressure through a semipermeable membrane Sterilisation – Destruction or removal PPB – Parts per billion is a unit equal leaving behind dissolved organic, of all living microorganisms. to one microgramme per kilogram dissolved ionic, and suspended of water. Numerically ppb are impurities. Storage tank – In water purification equivalent to one microgramme per systems, a container holding litre in dilute aqueous solutions. Sanitisation – Chemical and/ quantities of purified water. or physical processes used to PPM – Parts per million is a unit kill microorganisms and reduce Total dissolved solids (TDS) – A equal to one milligramme per contamination from microorganisms. measure of the total of organic and kilogram of water. Numerically ppm inorganic salts dissolved in water, are equivalent to one milligrammes Service deionisation(SDI) – obtained by drying residue at 180°C. per litre in dilute aqueous solutions. Deionisation service provided by exchanging cylinders containing Total organic carbon (TOC) – Total PPT – Parts per trillion is a unit equal to ion exchange resins, which have concentration of carbon present in nanogramme per kilogram of water. been regenerated or replaced at a organic compounds. regeneration station. PSG – Pure steam generator (CSG – Turbidity – The degree of cloudiness clean steam generator) Silt Density Index – Also called the of water caused by the presence Fouling Index (FI) is a test used to of suspended particles or colloidal Pyrogen – A category of substances, estimate the potential of the water material. Turbidity reduces the including bacterial endotoxins, which to block filters, derived from the rate transmission of light and is may cause a fever when injected or of blockage of a 0.45 micron–filter measured in Nephelometric Turbidity infused. under standard conditions. Units (NTU).

29 PHARMACEUTICAL PURE WATER GUIDE

Ultrafiltration – A process in which water is filtered through a polymeric membrane having a very fine pore structure.

Ultraviolet (Photochemical) – A process using short wavelength light to kill microorgamisms and cleave or oxidise organic molecules.

USP – United States Pharmacopoeia. The United States Pharmacopoeia (USP) is the official public standards setting authority for all prescription and over–the–counter medicines, dietary supplements, and other healthcare products manufactured and sold in the United States. USP sets standards for the quality of these products and works with healthcare providers to help them reach the standards. USP’s standards are also recognised and used in more than 130 countries.

Validation – Confirmation, through the provision of objective evidence, that requirements for a specific intended use or application have been fulfilled.

Verification – Confirmation, through the provision of objective evidence, that specified requirements have been fulfilled.

WFI – Water for Injection.

30 PHARMACEUTICAL PURE WATER GUIDE

SERVICE AND MAINTENANCE

We offer a variety of service and maintenance contracts to ensure continual compliance and the assurance that your Orion delivers the optimum performance.

We specialise in delivering unrivalled service and maintenance for your process water requirements through operational excellence to:

Safeguard critical process which rely on continuous supply of purified water

Minimise equipment failures and downtime

Ensure regulatory compliance

Health and safety is our number one priority

Maximise availability

Meet water quality and quantity requirements

Optimise operating costs ensuring environmental efficiency

Extend equipment life

3131 PHARMACEUTICAL PURE WATER GUIDE

PHARMACEUTICAL PURIFIED WATER PROCESS

PRETREATMENT

Primary Filtration Hardness Removal Oxidizer Removal Prefiltration

Activated Carbon Filters Cartridge

20-5 Micron Cartridge Filter Softeners (1x) Granular AC (GAC) Feed water Multimedia Filter (MM) Organic Scavenger (OS) Non & Backwashable Sand Filter (SF) Hot Water or Steam Sanitizable

+ 1-5 Micron Cartridge + Filter Sulfite Injection Antiscalant Injection Ultra Filtration (UF) Ultraviolet (UV)

PURIFIED WATER STORAGE & DISTRIBUTION WFI GENERATION & STORAGE / DISTRIBUTION

Heat Control Skid

Cooler Heater Still Generator WFI Storage Distribution

Multi Effect (MES) WFI Vapor Compression (VP) TANK Pure Steam Generator (PSG) + Sanitization Skid

Chemical Ozone PURIFIED Hot Water (85°C) WATER TANK Over Heated (121°C) Steam

+

32 PHARMACEUTICAL PURE WATER GUIDE

GENERATION TREATMENT

Bacteria Reduction Primary Treatment Polishing Bacteria Reduction Pyrogen Removal

Continuous Electro- deionization (CEDI) Ultraviolet (UV)

Single Pass Reverse Osmosis (RO) Ultra Filtration Ultraviolet (UV) Ceramic Membrane In-Situ Mixed Bed Hollow Fiber Membrane Deionizer (MB) Chemical Sanitizable Hot Water or Steam Sanitizable Sub-Micron Cartridge Twin Pass Reverse Filter (0.22) Osmosis (RORO) Off Site Regenerable Mixed Bed Deionizer (SDI)

PHARMACEUTICAL FACILITY WASTE WATER

Treated Water & Solids

Veolia Water Technologies comprehensive technical expertise. From pre- treatment, sludge treatment, incineration to air/odour treatment.

Actiflo™, Biosep™, Aquilair™, LED or MPPE®

33 PHARMACEUTICAL PURE WATER GUIDE

34 The written text, technical information and illustrations, contained in this document are the property of Veolia Water Technologies, and are protected by copyright law. The information is supplied without liability for errors or omissions. No part of The Pharmaceutical Pure Water Guide may be copied, reproduced, transmitted in any form or by any means, electronic, mechanical, magnetic, or manual including photocopying, recording, or information storage and retrieval systems or disclosed to third parties or used for any other purpose than the reader’s personal use without the express written permission has first been obtained from Veolia Water Technologies. Veolia Water Technologies reserves the right to alter without notice the text, technical information and illustrations contained in this guide.

This guide has been written by the experts of Veolia Water Technologies. Contacts: [email protected], [email protected]

Veolia Water Technologies Communications - 12/2020 (200228) Photo credits: © Veolia photo library / Christophe Majani D'Inguimbert. Veolia Water Technologies tel. +1-800-337-0777 www.veoliawatertech.com [email protected]