Pharmaceutical Water system and Qualification

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Aditi Shetye

October 18, 2023

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Disclaimer��

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The views and opinion expressed in this presentation are those of the author and do not necessarily represent official policy or position of Cipla.

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What to expect from the session…….��

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• Background to Water requirements
• Water Quality Specification
• Water treatment methods
• Good practices for water systems
• System sanitization and bioburden control
• Storage Vessels
• Water Distribution
• Qualification of water system
• Biofilm
• Sampling and testing of Pharmaceutical Water
• Pharmacopieal Specification
• Continuous System Monitoring
• Maintenance of water system

• System Review
• Inspection of water systems
• Case studies

Background to Water requirements..�

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Water is widely used substance in pharmaceutical industry. It is extensively used as raw material or starting material in production, processing and formulation of APIs, intermediates and finished pharmaceutical products, in the preparation of solvents and reagents, and for cleaning (e.g., washing and rinsing)..

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Different grades of water quality exist. The appropriate water quality, meeting its defined specification (such as described in a pharmacopoeia), should be used for the intended application.

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The grade of water used should take into account the nature and intended use of the intermediate or FPP and the stage in the manufacturing process at which the water is used.

Water for injections should be used, for example, in the manufacture of injectable products, such as dissolving or diluting substances or preparations during the manufacturing of parenteral products, and for the manufacture of water for preparation of injections

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The microbiological and chemical quality of water should be controlled throughout production, storage and distribution.

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Schematic Diagram - Generation and Distribution of Purified water and water for injection� Purified water Flow WFI flow�

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Water Quality Specification

Drinking Water:��

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Drinking-water may be derived from a natural or stored source.

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• Natural sources : springs, wells, rivers, lakes and seas.
• Public water supply system : off-site source, such as a municipality.
• Purchased in bulk and transported to the user: by water tankers (controls should be put into place to mitigate any associated risks)

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The condition of the source water should be considered when choosing a treatment to produce drinking- water.

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Typical processes to produce drinking-water : desalination; filtration; softening; disinfection or sanitization, such as by ozone or sodium hypochlorite (chlorine); iron (ferrous) removal; precipitation; and the reduction of concentration of specific inorganic and/or organic materials.

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The quality of drinking-water should be monitored routinely to account for environmental, seasonal or supply changes which may have an impact on the source water quality.

Purified Water:�

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PW should be prepared from drinking-water as a minimum-quality feedwater.

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Any appropriate, qualified purification technique, or sequence of techniques, may be used to prepare PW.

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PW could be prepared by, or any combination of these techniques

• ion exchange,
• reverse osmosis (RO),
• electro-deionization(EDI),
• ultrafiltration,.

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Purified water (BPW) should meet the relevant pharmacopoeial specifications for chemical and microbiological purity.

PW should have appropriate alert and action limits for chemical and microbiological purity determined from a knowledge of the system and data trending.

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Purified Water:�

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Aspects to be considered when configuring a water purification system or defining URS:

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• quality of feedwater and its variation over seasons;
• quantity of water required by the user;
• sequence of purification stages required;
• number and location of sampling points
• design of sampling points in such a way so as to avoid potential contamination;
• appropriate instrumentation to measure parameters such as flow, pressure, temperature, conductivity and total organic carbon;
• material of construction;
• sanitization strategy;
• interlocks, controls and alarms; and
• appropriate software, electronic data management, system security and audit trail.

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Purified Water:�

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Controls to minimize microbial contamination:

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• Maintenance of water flow at all times in the storage and distribution system to prevent water from stagnating;
• Control of temperature in the system, for example, by heat exchangers or room cooling in order to reduce the risk of microbial growth;
• Provision of ultraviolet disinfection at appropriate locations in the system;
• Use of water-treatment system components that can periodically be thermally sanitized above 70 °C for a defined period of time, or chemically sanitized using, for example, ozone, hydrogen peroxide and/or peracetic acid; and
• a combination of thermal and chemical sanitization, if required.

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Methods for sanitizing each stage of purification should be appropriate and validated. The removal of any agents used for sanitization should be proven.

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Water for Injection:�

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WFI is the highest quality of pharmacopeial Water for pharmaceutical use.

WFI is not a final dosage form. It is an intermediate bulk product suitable to be used as an ingredient during formulation.

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WFI may be prepared by distillation as the final purification step.

Alternatively, BWFI may be produced by means other than distillation, in conjunction with a single or double pass RO

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• deionisation,
• electro deionization,
• nanofiltration,
• ultrafiltration,
• water-softening,
• descaling, pre-filtration
• degasification,
• ultraviolet treatment,

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BWFI should have appropriate microbial and chemical alert and action limits

Water for Injection:�

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Aspects to be considered when configuring a water purification system or defining URS:

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• quality of feedwater and its variation over seasons;
• quantity of water required by the user;
• sequence of purification stages required, where appropriate;
• material of construction
• optimum generator size or generators with variable control to avoid over-frequent start/stop cycling;
• blow-down and dump functions;
• cool-down venting to avoid contamination ingress;
• appropriately located sampling points designed in such a way so as to avoid potential contamination;
• appropriate instrumentation to measure parameters as required;
• sanitization strategy;
• interlocks, controls and alarms; and
• electronic data storage, system security and audit trail.

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Disinfection

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Disinfection�

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Chlorination : Use Sodium Hypochlorite solution for bulk disinfection of raw water and for sustenance dosing.

The disinfection efficacy of Sodium hypochlorite depends on:

• pH
• Contact time
• Temperature

A free chlorine level of 0.2 – 0.5 ppm is adequate to control microbial growth

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Ozonation : Ozone is highly reactive oxidizer that can be used to reduce impurities such as microorganisms and organic carbons (ISPE 4.4.1)

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UV light treatment : Considered for Microbial Disinfection and Ozone Destruction

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Sodium Meta Bisulfite : typical chlorine reducing agent of choice for larger RO systems. Before water enters to RO membranes, it is very important that all oxidizing agents from water must be removed. Removs chlorine which is left after softener.

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Filtration

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Filtration�

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Disc filters : high rate inside-out filtration systems where the dirty water flows into a central drum, then out through discs. They are comprised of woven filter fabrics that remove solids from the influent stream.

Backwash: to remove the buildup on the filter

Sanitation: for minimizing the risk of microbial growth.

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Glass Filter: consists of Activated glass filtration media

Capable of eliminating even heavy metals from your input water like mercury, in addition to chlorine and fluorides.

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Multimedia Filters/ Multi Grade Filters: column filters containing one or multiple layers of filtration media to remove particulates/ suspended solids, colloidal silica and iron/manganese from a flowing stream of water. Multimedia typically consists of layers of anthracite, sand and garnet

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Ultrafiltration : Membrane based process for removal of particles/ suspended solids, microorganisms, colloidal matter and high molecular weight TOC upstream of final treatment. Usually operated with a reject stream and cleaned with a backwash and/or chemical agents.

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Activated carbon beds: Used to adsorb low-molecular weight organic material, bacterial endotoxins, and oxidizing additives such as chlorine and chloramine compounds, removing them from the water.

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Ion Exchange Softener

Electrodeionization

Reverse Osmosis

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Ion Exchange Softener: A cation exchange process that replaces hardness ions (calcium, magnesium, ammonium, barium and strontium) with sodium ions in a flowing stream of water though a resin bed. Hard ions are removed from the resin by a brine regeneration

Purpose of softening system shall avoid scaling of RO membranes due to presence of calcium and magnesium ions. Soft water further filter through SDI reduction filtration. It removes colloidal impurities and reduce SDI to less than 3 and enhance the working of RO unit.

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Continuous Electrodeionization : is a technology combining resins, ion selective membranes, and use of an electric field to continuously remove ionized species and regenerate the resins.

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Reverse osmosis : This process is used to remove the particles including ions from the water. The reverse osmosis system contains a semi-permeable membrane that allows passing the water and rejects the contaminants.

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WFI Generation

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WFI Generation Process:

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Multiple-Effect (ME) Distillation

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• ME stills use a staged evaporation and condensation process to produce WFI at a reduced energy consumption compared to an SE still.
• Utility steam is applied only to the first evaporator (effect), while the subsequent effects use the steam produced in the previous effect as the source of energy.
• Coolant is applied only at the final effect to condense Pure Steam into WFI.

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• Ensure Temp in Evaporator of Distillation unit to be >100 °C to prevent microbial level

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Good practices for water systems

Drinking water :�

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Materials of construction for storage, supply and distribution system should be selected based on the following requirements:

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• ability to operate at the temperatures/pressures required;
• lack of impact on the final water quality;
• resistant to sanitizing chemicals;
• threaded and flanged joints are permitted; and
• sample valves should preferably be of sanitary design.

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The system may have a design life at the end of which it should be replaced or adequately modified

Purified water and WFI:�

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Materials of construction for storage, supply and distribution system should be selected based on the following requirements:

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• Materials of construction: non-leaching, non-adsorbing, non-absorbing and resistant to corrosion.
• Orbital welding for Stainless steel systems
• Joints : made using sanitary connections, for example
• Threaded joints : not be permitted.
• Passivation: after initial installation and after significant modification
• Internal finish should be smooth.
• Flanges, unions and valves: hygienic or sanitary design.
• Surface roughness : 1.0 micrometre RA or lower
• Minimum slope of 1/100: to promote drainability.
• Pressure test, Spray ball functionality test
• Inline measurement: TOC, conductivity, pressure, flow and temperature.

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System sanitization and bioburden control

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Purified water and WFI:�

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Controls to reduce risk of contamination and proliferation of microbiological organisms:

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• Use of chemical and/or thermal sanitization procedures : validated procedure to ensure that the sanitizing process selected is effective and sanitizing agent has been effectively removed.
• Record of sanitization should be maintained
• Operation and maintenance of Systems at elevated temperatures (e.g. > 70 °C) : less susceptible to microbiological contamination
• Maintenance of a continuous circulation of water. Distribution systems have often been designed to operate with nominal flow velocities of >= 3 ft/s,
• Hygienic design: minimizing dead legs
• Installing pipework in a manner to allow for full drainage, if required : slope NLT 1/100.
• Use of ultraviolet lamps in the system

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Storage Vessels

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Purified water and WFI:�

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Storage vessels should be appropriate for their intended use.

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• Design and shape : to ensure drainage of water from the vessel,
• Material of construction
• Capacity : buffer capacity, between the steady state, water generation rate and the potentially variable simultaneous demand from user points, short-term reserve capacity in the event of failure of the water-treatment system or the inability to produce water (e.g. due to a regeneration cycle);
• Prevention of stagnant water in the vessel (e.g. the headspace where water droplets can accumulate)
• Use of a sprayball or distributor devices to wet the inner surfaces of the vessel;
• Bacteria-retentive, hydrophobic vent filters : tested for their integrity at appropriate intervals;
• Sanitary design pressure safety valves or bursting discs provided with external rupture indicators to ensure that loss of system integrity is detected;
• Design and sanitization : level indicators;
• Design and location of valves, sampling points and monitoring devices and sensors;
• Heat exchangers or jacketed vessels.

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Water Distribution

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Purified water and WFI:�

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• The water distribution system should be designed as a loop, with continuous circulation of BPW and BWFI.
• Filtration : not be used in distribution loops or at take-off user points.
• Where heat exchangers are used : continually circulating loops or sub-loops in order to avoid unacceptable static water in the system.
• Temperature reduction for processing purposes : minimum necessary time.
• Circulation pumps : sanitary design with the appropriate seals to prevent contamination of the system.
• Stand-by pumps : configured or managed to avoid zones where stagnant water is trapped
• Parallel pumps : no stagnant water remaining in a pump when the pumps is not being used.
• Components : identified and labelled.
• Direction of flow : indicated.

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Qualification of water system

Qualification of water system

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Various stages of qualification:

• URS, DQ, FAT, SAT
• IQ : Safety features, availability of components/parts, MOC, quantity, filters, pump, tank size, joints, welding
• OQ : Slope verification, passivation, hydro test for leakages, boroscopy test,
• PQ : Includes below phase wise validation

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A three-phase approach shall be used for validation for PW and WFI:

• Phase I
• Phase II
• Phase III

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Phase I

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• Testing for a period of at least two weeks from all sampling points.
• Chemical and microbiological testing in accordance with a defined plan;
• Sample, test and monitoring of the incoming feedwater to verify its quality;
• Sample, test and monitoring after each step in the purification process;
• Sample, test and monitoring at each point of use including the end of the distribution loop;
• Verification of operating ranges;
• Operating, cleaning, and maintenance;
• Sanitizing procedures and operating ranges;
• Demonstrate the consistent production and delivery of the required quality and quantity;
• Establishing provisional alert and action levels;
• Test-failure procedure.

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The system should be monitored intensively for its performance.

Water should not be used for product manufacturing during this phase.

Phase II

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• Testing for at least a further test period of two weeks after the satisfactory completion of Phase 1.
• The sampling program : same as in Phase 1.
• The use of the water for product manufacturing purposes : acceptable, provided that Phase 1 and ongoing Phase 2 data demonstrate the appropriate water quality

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The approach should also:

• Demonstrate consistent system operation within established ranges;
• demonstrate consistent production and delivery of water of the required quantity and quality when the system is operated in accordance with the SOPs.

Phase III

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• Phase 3 follows phase 2 ensuring that the duration of Phase I, 2 and 3 cover at least 12 months.
• The sample locations, sampling frequencies and tests : reduced according to a routine plan based on the established procedures and data from Phase 1 and Phase 2.
• Data trending: quarterly and a system review for the evaluation of system performance capability.
• The appropriate action to be taken where such a need is identified.
• Water can be used during this phase.
• The data and information obtained during Phase 3 should demonstrate the reliable performance of the system over this period of time covering the different seasons..

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Revalidation:

Frequency and extent of revalidation shall be determined using risk-based approach together with a review of historical data.

Revalidation in case of any major changes.

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Biofilm

Biofilm

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Most prevalent form of microbial life on earth.

• Planktonic: Suspended and floating in water
• Surface growth: Biofilms on wet surfaces

Survival advantage: nutrition, adapts, multiply

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Challenge:

• If attacked, only surface layers are killed
• Survivors regrow biofilm, nourished by dead biomass

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Impact of biofilms:

• Increased chemical impurities in final water
• Microbial contamination in final water
• Impacts finished product

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Pharmaceutical Water Sampling

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Design to control biofilm:

• Re-chlorination of incoming water
• Avoid stagnant areas
• Design automatic operations
• Heat sanitization
• Avoid designing excess capacity
• Avoid creating un-sanitizable nooks: threaded fittings, ball valves, gasketed joints
• Design internal recirculation loops to keep water moving during non-use periods
• Design appropriate reject/blowdown rates to avoid
• Over-concentrating contaminants
• Install sanitary/sanitizable sampling port
• Install spray balls to sanitize entire tank headspace
• Use vent filters on tanks
• Use level controllers, not overflow ports on tanks
• Backwash beds often
• Periodically replace

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Sampling and testing of Pharmaceutical Water

Pharmaceutical Water Sampling

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When water is used for pharmaceutical purposes, it needs to be tested to ensure that it meets monograph requirements or other specifications for applicable CQAs.

When water is extracted for sampling purposes at any point in a system for any reason, proper sampling is the key to ensuring that the collected sample accurately represents the quality of the water at that point in the system.

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Sampling technique

As a general rule, and to minimize contamination during production water use, it is recommended that water be flushed (e.g., for at least 30 seconds at a velocity of at least 8 feet per second or an alternative validated technique) through the outlet and connectors to ensure that bacteria are flushed from the walls of the hose, discharge piping and outlet valve prior to use.

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As per USP 1231 “Fully open valve, flush (at >8 ft/s velocity within the valve and connector) for at least 30 seconds typically provides sufficient shear forces to adequately remove any fragile biofilm structures”

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Pharmaceutical Water Sampling

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QC sampling is intended to reflect the quality of water that is being used. These samples should be collected at the true point of use; that is, where the water is delivered for use.

The water delivery process and components used for QC sampling : identical to manufacturing practices at every system outlet for the QC sample to mimic the quality of water being used by accumulating the same chemical and microbial contaminant levels it would during actual use from that outlet location.

Where permanent connections from the water system to equipment are present, accommodation should be made in the design to collect samples from locations as close to the equipment as possible.

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Chemical Attributes:

Chemical contaminant dissolved in water is detected by conductivity and TOC which are uniformly distributed in the water throughout the water system.

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Microbial Attributes:

Microbial attributes are not uniformly distributed in the water system.

Microorganisms originated from the biofilms in the purification and distribution system releases more or less uniform levels of organisms in circulating water.

Local biofilms developing at the point of use releases the organisms only in water delivered through that point of use.

Sample collector training

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�The vast majority of variations in results can be traced back to variations in how samples are taken. Without rigorous training and continual review, variations in water quality data may reflect variations in sampling technique rather than actual variations in water quality. This introduces increased variability to collected data.

Sample collector should be properly trained and should have demonstrated their ability to collect sample following approved sample collection SOP.

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Sample collector should practice good hand hygiene and health practice expected to be followed in any GMP facility.

Appropriate GMP gowning as per area to be worn.

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Routine Sampling Plan For Water

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Pharmacopieal Specification

Chemical and Microbiological Tests Requirements

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Continuous System Monitoring

Continuous Monitoring..

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• A monitoring plan : samples collected in accordance with a written procedure.
• Online monitoring : Flow, pressure, and temperature, conductivity and TOC
• Offline testing : Physical, chemical and microbiological attributes
• Sampling : User points and dedicated sample points.
• Tests : to meet the relevant pharmacopoeia specification
• Trending : At defined intervals, for example, monthly, quarterly and annually, to identify trends.
• Alert and action levels : Established based on historically reported data.
• Adverse trends and out-of-limit results : Investigated for the root cause, followed by the appropriate corrective and preventive actions.
• Microbial contamination of WFI : Micro-organism to be identified.

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Maintenance of water system

Maintenance..

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• Defined frequency for system elements e.g. filters, instruments, gauges;
• Calibration programme;
• SOPs for specific tasks;
• Control and storage of approved spare parts;
• Preventive maintenance and maintenance plan and instructions, including cleaning after maintenance;
• Review and approval of systems for use upon completion of work;
• Record and review of problems and faults during maintenance

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System Review

System Review..

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Review to be conducted at defined interval

• changes made since the last review;
• system performance trends and capability;
• quality trends;
• failure events and alarm history;
• investigations;
• out-of-specification and out-of-limit results;
• alert and action limits;
• assessing compliance with current GMP requirements for WPU systems;
• verification of documentation being current;
• maintenance and calibration history;
• records such as log books and electronic data; and
• the appropriateness of the software and the computerized system linked to the water system, for example, SCADA, including audit trail, authorized users with access and privileges.

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Inspection of water system

What to look for…

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• dead legs
• filter
• pipes and fittings

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• storage tanks
• by-pass lines
• non return valves

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Check pipes and pumps

• hygienic couplings
• welded pipes
• hygienic pumps
• hygienic �sampling points
• acceptable floor
• no leaks

• RO
• heat exchangers

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Take the drawing and walk around the entire system:

• pumps
• UV lights
• sample points

What to look for…

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• UV light – monitoring performance , lamp life and intensity
• Specifications for acids, alkalis for DI and sodium chloride for water softener
• Valves: “Normally open” and “normally closed”
• Validation of WFI system
• Rouging of water systems
• Spray ball efficacy
• Activated carbon bed sanitization
• Temperature-compensated conductivity meters
• Influence of plastic pipe adhesive on TOC
• Non-condensable gases in pure steam
• Check air filters : integrity testing, replacement frequency
• Check burst discs
• Maintenance of pump seals and O rings
• Check condition of equipment :Rusting

Water Systems Guide�

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1. ISPE Baseline Guide: Water and Steam systems, Volume 4, 2019
2. ISPE Good Practice Guide: Ozone Sanitization of Pharmaceutical Water Systems
3. ISPE Good Practice Guide: Approaches to Commissioning and Qualification of Pharmaceutical Water and Steam Systems
4. FDA Pharmaceutical cGMPs for the 21st Century – A Risk-Based Approach Final Report, US Food and Drug Administration (FDA), September 2004, www.fda.gov.
5. International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH), www.ich.org.
6. Indian Pharmacopeia (IP)
7. United States Pharmacopeia–National Formulary (USP-NF), www.usp.org/USPNF.
8. European Pharmacopoeia (Ph. Eur.), www.edqm.eu.
9. ASME BPE-2016 Bioprocessing Equipment
10. Pharmacopoeia of the People’s Republic of China, Chinese Pharmacopoeia (ChP), www.wp.chp.cn.
11. WHO Technical Report Series, No. 970, 2012, Annex 2, World Health Organization,
12. PDA TR 69
13. Schedule M
14. European Medicines Agency (EMA), www.ema.europa.eu/en.
15. Pharmaceutical Inspection Convention and scheme (PIC/S)
16. International Organization for Standardization (ISO), www.iso.org.

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Water Systems Guide�

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Guidance, Documents and Literature referred:

12. Pharmacopoeia of the People’s Republic of China, Chinese Pharmacopoeia (ChP), www.wp.chp.cn.
13. WHO Good Manufacturing Practices: Water for Pharmaceutical Use. WHO Technical Report Series, No. 970, 2012, Annex 2, World Health Organization, https://www.who.int/medicines/areas/quality_safety/quality_ assurance/expert_committee/TRS-970-pdf1.pdf.
14. PDA TR 69
15. European Medicines Agency (EMA), www.ema.europa.eu/en.
16. European Directorate for the Quality of Medicines & Health Care (EDQM), www.edqm.eu.
17. Japanese industrial Standards
18. China, National Medical Products Administration (NMPA)
19. World Health Organization
20. Pharmaceutical Inspection Convention and scheme (PIC/S)
21. ASME
22. International Organization for Standardization (ISO), www.iso.org.

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Case study- 1

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You are given a schematic drawing of a water system to discuss

List any problems.

Case study – 2

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Problem statement: Conductivity is above alert/ action limit at supply point to loop.

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Investigation:

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Root cause:

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Potential effect:

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Controls/ CAPA:

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THANK YOU!!

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That is what learning is. You suddenly understand something you’ve understood all your life, but in a new way.” — Doris Lessing

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