WATER SYSTEM IMPORTANCE OF WATER Water is widely

WATER SYSTEM

IMPORTANCE OF WATER Water is widely used as a raw material, ingredient and solvent in the processing formulation and in the manufacture of pharmaceutical products, Active pharmaceutical ingredients and in intermediates. There is no single specification as it would unnecessarily burden some users with irrelevant specifications Water systems need to be operated and maintained in a controlled manner that requires the system to be validated as certain analysis like microbial analysis needs time.

DESIGN OF WATER SYSTEM Major considerations Water quality Product requirements Dosage form Usage(Production or cleaning) Internal quality Regulatory requirements Use point criteria Delivery pressure and temperature Delivery flow rate Utilization schedule Level of automation System criteria Storage Feed water quality Generation rate Existing capacity Cost factors

SOURCE WATER AND PRETREATMENT To ensure adherence to minimal chemical and microbiological quality attributes water source should meet the requirements of NPDWR(40 CFR 141) or drinking water regulations of European union or Japan or WHO water guidelines. Pretreatment unit operations should be designed and operated in such a way to adequately remove the disinfectant, drinking water Degradable by products and objectionable degradants.

CATEGORIES OF WATER General categories of water Bulk water which are typically produced onsite when they are used Packaged water which are produced, packaged and sterilized to preserve microbial quality throughout their packaged shelf life Other waters like water with no monograph bulk waters with names given for descriptive purposes. BULK WATER TYPES: v Drinking Water. v Purified Water v Sterile Purified v Water for Injection v Sterile Water for Injection v Bacteriostatic v Sterile Water for Irrigation v Sterile Water for Inhalation

METHOD OF PRODUCTION Production of pharmaceutical water employs sequential unit operations (processing steps)that address specific water quality attributes and protect the operation of subsequent treatment steps. The final unit operations used to produce Water for Injectionhave been limited to distillation and reverse osmosis

METHOD OF PRODUCTION Type I. P B. P USP Drinking/ Potable water As per National Requirement Purified Distillation/Ion exchange Highly Purified WFI NA Distillation (Discard first portion) De-ionization, distillation, ion exchange, RO Double pass RO coupled with UF/Deionization Distillation De-ionization, distillation, ion exchange, RO NA Distillation/RO

SPECIFICATIONS OF WATER Parameter Purified Water Highly purified IP USP BP IP BP USP 1. 3 NS 1. 3 <500 ppb NS <500 ppb BP Conductivity NS 5. 1(25 °C) TOC Not Specified (NS) WFI Endotoxin Not Specified 0. 25 EU/ml Microbial 100 cfu/ml 10 cfu/100 ml

SELECTION OF UNIT OPERATIONS The selection of specific unit operations and design characteristics for a water system should take into consideration the quality of the feed water, the technology chosen for subsequent processing steps, the extent and complexity of the water distribution system, and the appropriate compendial requirements. Selection can be categorised as Pre treatment: Filtration Activated carbon Softener Microbial control by UV, ozone or chlorine Final treatment: CEDI, Reverse osmosis, Ion exchange

PREFILTRATION The prefiltration uses sieving effect to remove solid contaminants down the size of 710 micrometers. Granular or cartridge filters are used for pre filtration. They remove solid contaminants from the water supply and protect downstream system components from contamination Unit and system configurations vary widely in type of filtering media and location in the process

Design and operational issues and Control measures Design and operational issues Control measures channeling of the filtering media Pressure and flow monitoring Blockage from silt Backwashing, sanitizing, and replacing filtering media. Microbial growth and filtering-media loss sizing of the filter to prevent channeling or media loss resulting from inappropriate water flow rates.

ACTIVATED CARBON BEDS Activated carbon beds adsorb low-molecular-weight organic material and oxidizing additives, such as chlorine compounds, and remove them from the water.

DESIGN AND OPERATIONAL ISSUES AND CONTROL MEASURES Design and operational issues Control measures Potential for hydraulic channeling Backwashing and maintaining appropriate high water flowrates Inability to be regenerated in situ Testing for adsorption capacity and frequent replacement of the carbon bed. Propensity to support bacteria growth, shedding of bacteria, endotoxins, organic chemicals and fine carbon particles. Appropriate high water flowrates, sanitization with hot water or steam

SOFTENERS Water softeners remove cations such as calcium and magnesium that interfere with the performance of downstream processing equipment such as reverse osmosis membranes, deionization columns and distillation units. If ammonium removal is one of the purpose then the softener must be located downstream of the disinfectant removal system. Water softener resin beds are regenerated with sodium chloride solution (brine).

Strong Acid Cationic Resin Typical Cations + H 3 O -S R Na Ca 2+ 3 O -S H R Polymeric Resin Na+ Mg 2+ K+ R-SO 3 H R-SO - H+ Metals 3 Cu 2+ RSO Ca 2+ 3 H+ Fe 2+ Zn 2+

DESIGN AND OPERATIONAL ISSUES AND CONTROL MEASURES Design and operational issues Control measures Microorganism proliferation, channeling due to inappropriate water flow rates Use of microbial control devices (e. g. , UVand chlorine) and flow rate monitoring Organic fouling of resin, fracture of the resin beads Recirculation of water during periods of low water use, , appropriate regeneration frequency, effluent monitoring (hardness), and downstream filtration to remove resin fines. Contamination from the brine solution used for regeneration. periodic sanitization of the resin and brine system

DEIONIZATION • • v v Deionization (DI), electrodeionization (EDI)and Electrodialysis (EDR) are effective methods of improving the chemical quality attributes of water by removing cations and anions. DI systems have charged resins that require periodic regeneration with an acid and base. The regeneration may be cationic resins are regenerated with either hydrochloric or sulfuric acid, which replace the captured positive ions with hydrogen ions. Anionic resins are regenerated with sodium or potassium hydroxide, which replace captured negative ions with hydroxide ions. Electrodeionization (EDI)

ELECTRODIALYSIS Electrodialysis (EDR): Electrodialysis (EDR)is a similar process that uses only electricity and selectively permeable membranes to separate, concentrate, and flush the removed ions from the water stream.

DESIGN AND OPERATIONAL ISSUES AND CONTROL MEASURES Concerns for all forms of deionization units Design and operational issues Control measures Microbial and endotoxin control Recirculation loops, microbial control by UV light Chemical additive effect on resins and membranes and loss, degradation and fouling of resin. Resin testing , microporous filtration of mixing air, microbial monitoring, Regeneration frequency, channeling , complete resin separation for mixed bed regeneration. Ensuring regeneration chemicals contact all internal surfaces and resins. Rechargeable canisters can be the source of contamination and should be carefully monitored.

REVERSE OSMOSIS Reverse osmosis (RO)units employ a semipermeable membrane and a substantial pressure differential to drive water through the membrane to achieve chemical, microbial, and endotoxin quality improvement. Pretreatment and system configuration variations may be necessary, depending on source water to achieve desired performance and reliability.

KEY TERMS IN RO SYSTEMS q q q q Permeate : The “purified” product water exiting the system. Concentrate : The concentrated salt solution exiting the system. Feed Flow: The total flow rate of the source water pumped in the system. Recovery : The percentage of permeate achieved in a system, % Recovery = permeate flow/feed flow x 100. q q Rejection: The percentage of dissolved solids removed from the source water by the membrane.

DESIGN CONSIDERATION A major factor in RO is the permeate recovery rate ie the amount of water passing through the membrane compared to the water rejected. Increased rerecoveries with high pressures in order to reduce the volume of rejected water will result reduced permeate purity. If increased pressure are needed to achieve the same permeate flow this indicates a partial membrane failure.

DESIGN AND OPERATIONAL ISSUES AND CONTROL MEASURES Design and operational issues Control measures Membrane material sensitivity to bacteria and sanitizing agents Periodic sanitisation, monitoring of microbial levels and TOC Seal integrity Appropriate membrane selection and integrity challenges

DISTILLATION Distillation units provide chemical and microbial purification via thermal vaporization, mist elimination, and condensing. A variety of designs are available, including singleeffect, multiple-effect, and vapor compression. The latter two configurations are normally used in larger systems because of their generating capacity and efficiency. Distilled water systems may require less rigorous control of feed water quality than do membrane systems.

DESIGN AND OPERATIONAL ISSUES AND CONTROL MEASURES Design and operational issues Control measures Carryover of impurities Reliable mist elimination, and sensing with automated diversion of unacceptable quality water to the waste stream Evaporator flooding visual or automated high-water-level indication Stagnant water, pump and compressor seal design, use of sanitary pumps and compressors, proper drainage, blow down control conductivity (quality) variations during startup and operation. use of on-line conductivity

OTHER UNIT OPERATIONS Microbial retentive filters charged filter media Organic scavenging devices

STORAGE TANKS Storage tanks are included in water distribution systems to optimize processing equipment capacity. Storage also allows for routine maintenance while maintaining continuous supply to meet manufacturing needs.

KEY DESIGN PRINCIPLES Design should take care of peak flow requirements Must maintain the feed quality till the end user point. Design and operation considerations are needed to prevent the development of biofilm , to minimize corrosion, to aid in the use of chemical sanitization of the tanks and to safeguard mechanical integrity. There should be minimum changes in water temperature.

DESIGN AND OPERATIONAL ISSUES AND CONTROL MEASURES Design and operational issues Control measures Improper wetting of the tank closed tanks with smooth interiors and the ability to spray the tank head space changes in water levels Hydrophobic microbial retentive membrane filter fitted onto an atmospheric vent.

MICROBIAL GROWTH FACTORS AND ELIMINATION Microbial growth factors Elimination measures Stagnant conditions and areas of low flow rate Continuous turbulent flow Proper slope Ensuring no leaks Maintaining positive system pressure for draining Temperature that promote microbial growth Elevated temperatures Rough surfaces Smooth clean surface that minimizes nutrient area Other measures: Frequent draining, flushing and sanitization Air breaks in drain piping Electoplating lines Reduced dead legs Using UV light

DISTRIBUTION LOOP Distribution configuration should allow for the continuous flow of water in the piping by means of recirculation or should provide for the periodic flushing of the system. Components and distribution lines should be sloped and fitted with drain points so that the system can be completely drained. In ambient temperature distribution systems, particular care should be exercised to avoid pocket areas and provide for complete drainage. Water exiting from a loop should not be returned to the system. Distribution design should include the placement of sampling valves in the storage tank and at other locations such as the return line of the recirculating water system

DISTRIBUTION LOOP Corrosion hazards Elimnation Interangular corrosion • Keeping internal strain as low as possible • Select tubing with good concentricity • Avoiding joining dissimilar metals and cyclic bending • Passivation of line Galvanic corrsosion Contact corrosion Pitting or pin hole corrosion Stress corrosion crackling

KEY DESIGN CONSIDERATIONS Continuously re circulated systems are easier to maintain. Pumps should be designed to deliver fully turbulent flow conditions to retard the development of bio films. In distribution systems, where the water is circulated at a high temperature, dead legs and low-flow conditions should be avoided, and valved tie-in points should have length-to-diameter ratios of 6 or less. Direct connections to processes or auxiliary equipment should be designed to prevent reverse flow into the controlled water system. The distribution system should permit sanitization for microorganism control. The system may be continuously operated at sanitizing conditions or sanitized periodically.

VALIDATION APPROACH Validation plan for a water system typically includes the following steps: Establishing standards for quality attributes and operating parameters. Defining systems and subsystems suitable to produce the desired quality attributes from the available source water. Selecting equipment, controls, and monitoring technologies. Installation Qualification stage: Developing an IQ stage consisting of Instrument calibrations Inspections to verify that the drawings accurately depict the as-built configuration of the water system, and, Special tests to verify that the installation meets the design requirements. (wherever necessary)

SUPPLEMENTATION OF INSTALLATION The validation approach can be supplemented with schematic diagram, written system specifications, detailed design drawings, vendor manuals and drawings. Isometric location and number of welds, relative elevation slope of lines and points of drainage. Field inspection and test reports which includes Cleaning Passivation procedure and record weld parameter documentation and inspection reports Slope verification and verification of absence of dead legs.

OPERATION STAGE Operation Qualification stage: Developing an OQ stage consisting of Tests and inspections to verify that the equipment, system alerts, and controls are operating reliably and that appropriate Alert and Action Levels are established. Qualification test should include verification of functions specification temperature distribution system velocity and initial water quality determination.

PERFORMANCE QUALIFICATION Developing a prospective PQ stage to confirm the appropriateness of critical process parameter operating ranges. A concurrent or retrospective PQ is performed to demonstrate system reproducibility over an appropriate time period. During this phase of validation, Alert and Action Levels for key quality attributes and operating parameters are verified. This can be done in three phases

Phase I Frequency Develop appropriate operating ranges 2 -4 weeks Develop and fimalize operating , cleaning and maintenance procedures Demonstrate production and delivery of water of the required quality

Phase II Frequency Demonstrate consistent operation within established ranges 2 -4 weeks Demonstrate consistent production and delivery of water of the required quality Phase III Frequency Demonstrate extended performance 1 year Ensure potential seasonal variations are evaluated and treated.

AUTOMATED SYSTEMS Local instrumentation with manual control Semi automated systems Complete Automated systems Design considerations Water contact surfaces should be compatible Sensors should be of sanitary design Instruments can be installed in direct or side stream Dead legs should be avoided

VALIDATION MAINTENANCE PROGRAM Supplementing a validation maintenance program (also called continuous validation life cycle)that includes a mechanism to control changes to the water system and establishes and carries out scheduled preventive maintenance, including recalibration of instruments. In addition, validation maintenance includes a monitoring program for critical process parameters and a corrective action program. Instituting a schedule for periodic review of the system performance and requalification.

ONLINE INSTRUMENTATION Test parameters: Conductivity (Off line method) Stage 1: Use inline or grab sample and measure conductivity and operating temperature Stage 2: Vigorous mixing and temperature normalization to 25± 1ºC Stage 3: Retest within 5 minutes while maintaining the temperature. Add 0. 3 ml of potassium chloride solution and determine the p. H to nearest 0. 1 units Location: Last point of use before return line Conductivity (Online method) Non temperature compensated measurements are to be calculated Compensated measurements are for process control and monitoring Level: Level was not regarded as a critical parameter and monitored for information only.

ONLINE INSTRUMENTATION TOC: TOC is a measure of the carbon dissolved in water in the form of organic compounds. Online TOC meters may be used for final quality testing but for critical assurance testing of purified water of USP purified water and WFI Instrument precision System suitability Test methodology Calibration procedure must meet USP requirements. Pressure: Pressure may be monitored and controlled to ensure optimum equipment operation. Monitoring Dp indicates back wash or membrane replacement is needde.

ONLINE INSTRUMENTATION p. H: For high conductivity water p. H measurements are easy. Online instruments are not preferred for final quality control and used for process monitoring. Flow: Water flow rate or velocity may help to reduce the microbial growth. It is commonly verified on start up but not continuously monitored. Temperature: Temperature is considered critical wherever the temperature is controlled or heat sanitization is used to ensure proper system operation or effective sanitization.

SANITISATION Periodic sanitization of storage and distribution system is generally required which may be Chemical method: Various chemicals or chemical combinations are used to sanitize storage or distribution systems. The critical aspect of this is the complete removal of sanitizing agent from the system. Heat method: Heating circulating water in the distribution system to 80 ± 3º C and holding it for a validated period of time. Ozone method: In this ozone is continuously circulated and removal of ozone is done by use of UV radiation.

KEY TERMS Dead leg: A dead leg is any area in a piping system where water can become stagnant and where water is not exchanged during flushing. Bacteria in dead-end pipe lengths and crevices are protected from flushing and sanitization procedures and can recontaminate the piping system. Modern piping design limits the length of any dead-end pipe to 6 times the pipe’s diameter (even shorter dead legs are preferred). This is the six diameter rule.

KEY TERMS Passivation : The means of obtaining the loss of chemical reactivity exhibited by certain metals under special environment conditions. ie The state in which a stainless steel exhibits a very low corrosion rate. Passivation generates oxide film that covers and protects the surface of a metal. Rouge: It is a form of surface corrosion that occurs in some stainless steel water systems. This phenomenon occurs in system that offers a more corrosive environment. Heat number: Each melt of steel is assigned a heat number to identify the mix or exact composition of the steel. The variation will change the melting point and electric current input of weld machine considerably.

KEY TERMS Borescope: It is done for verification of weld quality. It is a fiber optic instrument with a monitor used for inspecting the weld inside a pipe or tubing. Welder qualification: Each welder performing welding on certain metals must be qualified for the type of the metal and welding. The American Society of Mechanical Engineers and American Welding Society have welding procedures for welder qualification. Qualified welder should have the certificate for certain type of weld.

KEY TERMS Grit finish: Method used to define surface finishes which is the number of scratch lines per inch of surface produced. It is not a true measure of surface quality as it does not give depth of scratch lines. Electropolishing: It is done to improve the mechanical finish by rounding off sharp peaks of scratch lines. Roughness Ra: Amplitude parameters characterize the surface based on the vertical deviations of the roughness profile from the mean line. Ra, is expressed in units of height.

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