Pharmaceutical Purified Water System Guide.
This document provide detail information about Pharmaceutical Purifued Water system it’s Components and Design Considerations principle of working of ion exchange resin activated charcoal bed RO and electro deionization system. Microbial alert and action limits and sanitation of pharmaceutical Purified Water System.
Pharmaceutical water systems play a critical role in the pharmaceutical industry, as water is a crucial component in the production of drugs, and other pharmaceutical products. The quality and purity of water used in pharmaceutical manufacturing are essential to ensure the safety, efficacy, and compliance of the final products.
Components of a Pharmaceutical Purifued Water System:
Ion Exchange Resins:
Ion exchange resins are essential components used to remove ions and impurities from the water. These resins consist of small beads with functional groups that attract and exchange ions present in the water. Cation exchange resins remove positively charged ions like calcium, magnesium, and sodium, while anion exchange resins remove negatively charged ions like chloride, sulfate, and nitrate. The combination of both cation and anion exchange resins is known as a mixed bed, which produces highly purified water.
Mixed Bed Column:
As mentioned earlier, the mixed bed column contains a combination of cation and anion exchange resins. It is the final polishing step in the water purification process, producing ultrapure water suitable for critical pharmaceutical applications.
Activated Charcoal Column:
Activated charcoal, also known as activated carbon, is used to remove organic impurities, chlorine, and certain volatile substances from the water. The porous structure of activated charcoal provides a large surface area for adsorption, effectively purifying the water.
Reverse Osmosis (RO) Column:
Reverse osmosis is a filtration process that uses a semi-permeable membrane to remove a wide range of contaminants, including dissolved salts, bacteria, viruses, and organic compounds. The RO column plays a crucial role in generating high-quality water by forcing water through the membrane, leaving impurities behind.
Electrodeionization (EDI) System:
The Electrodeionization (EDI) system employs a combination of ion exchange resins and electrical currents to remove ionized impurities from the water continuously. This process is effective in producing water with extremely low conductivity and high purity, making it suitable for pharmaceutical applications.
Material of Construction:
The materials of construction for pharmaceutical water systems are selected based on their compatibility with the purified water and their ability to withstand the cleaning and sanitization procedures.
Common materials used include:
Stainless Steel: 316 L Often used for components in contact with purified water due to its corrosion resistance and ease of cleaning.
Polyvinyl Chloride (PVC) and Polypropylene (PP): Used for non-contact components such as piping and fittings.
Teflon (PTFE): Used for gaskets and seals due to its excellent chemical resistance. Air vent filter used for storage thanks are made with teflon.
Electropolished Surfaces: Stainless steel components can be electropolished to achieve a smoother surface with reduced crevices, minimizing the potential for bacterial growth.
Quality Requirements and Design Considerations for Pharmaceutical Purifued Water System:
Piping Requirement and Bends:
Pharmaceutical water systems often use smooth, seamless piping to minimize the risk of microbial contamination and facilitate easy cleaning.
Bends in the piping should be minimized, as they can create dead legs (sections with stagnant water) where microbial growth may occur. When bends are necessary, they should have a large radius to reduce pressure drop and avoid flow disruption.
Loop System:
A closed-loop system is commonly used in pharmaceutical water systems to maintain water circulation and prevent stagnation.
The loop design must incorporate proper sizing, flow rates, and backflow prevention mechanisms to ensure consistent water quality.
Slope:
Piping should be sloped appropriately to facilitate drainage and prevent the accumulation of water in low points.
Proper slope ensures that the system can be effectively drained and sanitized during routine maintenance.
Dead Lag Volume:
Dead lag volume refers to the volume of water that remains stagnant in the system after a change in water flow or during system shutdowns.
To minimize dead lag volume, the system should be designed with minimal dead-end piping and appropriate valve configurations to flush out stagnant water during startup.
In conclusion, a well-designed pharmaceutical water system is crucial for ensuring the production of high-quality pharmaceutical products. The combination of ion exchange resins, activated charcoal, reverse osmosis, mixed bed columns, and electrodeionization provides multiple purification stages to achieve the required level of purity. Material selection, proper piping design, and consideration of dead lag volume are essential factors to prevent contamination and maintain the system’s reliability and efficiency. Compliance with regulatory guidelines, such as those provided by the United States Pharmacopeia (USP) or other relevant authorities, is also crucial to meet industry standards and ensure patient safety.
Electrodeionization (EDI) System for Pharmaceutical Purifued Water System:
Introduction to Electrodeionization (EDI) System:
Electrodeionization (EDI) is a state-of-the-art water purification technology that has gained significant popularity in various industries, including pharmaceutical manufacturing. It is an advanced and eco-friendly process that produces high-purity water by removing ionized impurities from the water stream without the need for chemicals or regeneration.
Working Principle of Electrodeionization (EDI) System:
The EDI system operates based on the principles of ion exchange and electrodialysis. It consists of a stack of alternating ion exchange membranes and ion-exchange resin-filled compartments. The process involves three main components: feedwater, ion exchange membranes, and electrical current.
Feedwater: The feedwater, which typically comes from a reverse osmosis (RO) system, enters the EDI unit, and it contains a small amount of remaining ionized impurities.
Ion Exchange Membranes: The stack of ion exchange membranes, alternating between cation- and anion-selective membranes, separates the feedwater into compartments.
Electrical Current: When an electrical current is applied across the ion exchange membranes, it generates electrically charged species called ions. The cation exchange membrane allows positively charged ions (cations) to pass through, while the anion exchange membrane allows negatively charged ions (anions) to pass through.
As the feedwater flows through the compartments, the ion exchange membranes attract and trap the cations and anions, effectively removing them from the water stream. The trapped ions are then transported to concentrate compartments by the electrical current.
In the concentrate compartments, a continuous flow of water sweeps away the concentrated ions, preventing the accumulation of impurities and enabling continuous purification.
Limits of Conductivity in EDI Systems in Pharmaceutical Purified Water System:
Electrodeionization systems are capable of producing ultrapure water with extremely low conductivity. The limits of conductivity depend on several factors, including the design of the EDI unit, the feedwater quality, and the applied electrical current. In most pharmaceutical applications, EDI systems can achieve a conductivity of less than 1 microsiemens per centimeter (μS/cm). Some advanced EDI systems can even achieve conductivity levels as low as 0.1 μS/cm or less.
Reject control system / Automatic Dumping System in Pharma Water Systems:
One of the critical aspects of EDI operation in pharmaceutical water systems is the automatic dumping system, also known as the reject control system. This system is designed to handle fluctuations in the feedwater quality and prevent any risk of contamination in the final product.
Working of Automatic Dumping System:
Real-Time Monitoring: The automatic dumping system continuously monitors the quality of the purified water produced by the EDI unit, typically measuring parameters such as conductivity and resistivity.
Quality Thresholds: The system is pre-set with specific quality thresholds. If the monitored water quality exceeds the predetermined limits, it indicates a potential issue with the EDI unit or feedwater quality.
Action Triggering: Once the predefined quality threshold is crossed, the automatic dumping system is triggered to divert a portion of the incoming feedwater from the EDI unit’s feed stream. This water, known as “reject” or “purge” water, contains higher levels of impurities.
Flush and Dump: The reject water is used to flush out any accumulated impurities or fouling materials from the EDI unit, ensuring that the water quality remains within acceptable limits.
Resuming Normal Operation: After the flushing process, the automatic dumping system resumes normal operation, allowing the purified water production to continue.
The automatic dumping system plays a vital role in maintaining the consistency and quality of the purified water by preventing any contamination events and ensuring continuous purification.
The Electrodeionization (EDI) system is a cutting-edge technology that has revolutionized water purification in pharmaceutical water systems. By combining ion exchange and electrodialysis principles, the EDI system can produce ultrapure water with low conductivity levels. The automatic dumping system further enhances the reliability of the EDI unit by monitoring and responding to variations in feedwater quality, ensuring the continuous production of high-quality pharmaceutical-grade water. As the pharmaceutical industry continues to evolve, EDI systems will remain an integral part of the manufacturing process, upholding the highest standards of purity and compliance.
Microbial Aspects, Contamination Control, and Hot Water Circulation Loop
Maintaining the microbial aspects of the water system is of utmost importance to prevent contamination and ensure the safety and efficacy of the final pharmaceutical products.
Microbial Aspects of Pharmaceutical Water Systems:
Microbial contamination in pharmaceutical water systems can arise from various sources, including the water source itself, the environment, equipment, and personnel. Common microbial contaminants include bacteria, fungi, algae, and viruses. These microorganisms can compromise the quality of the water and potentially lead to product contamination or even pose health risks to patients if administered in pharmaceutical products.
Contamination Control in Pharmaceutical Water Systems:
To control microbial contamination in pharmaceutical water systems, several measures should be implemented:
Design and Materials Selection: The pharmaceutical water system should be designed with smooth, crevice-free surfaces and materials that are resistant to microbial growth. Stainless steel, with electropolished surfaces, is commonly used due to its non-porous nature and ease of cleaning.
Pre-Treatment: Proper pre-treatment methods, such as filtration and chlorination, are essential to reduce microbial load before entering the water purification system.
Continuous Monitoring: Regular monitoring of water quality, including microbiological testing, helps detect any deviations and implement corrective actions promptly.
Sanitization Procedures: Routine sanitization procedures are crucial to eliminate and control microbial contaminants in the water system.
Sanitization Procedures in Pharmaceutical Purifued Water Systems:
Sanitization procedures are essential to maintain the integrity and purity of the water system. Common sanitization methods include:
Hot Water Sanitization: Hot water sanitization is one of the most common methods used in pharmaceutical water systems. It involves circulating hot water through the system at elevated temperatures for a specified period to kill microorganisms.
Chemical Sanitization: Chemical agents, such as sodium hypochlorite, ozone, can be used to disinfect the water system effectively. These chemicals are carefully selected to ensure compatibility with the water system and safety for the final pharmaceutical product.
Steam Sterilization: Steam sterilization is employed for specific components or parts that can withstand high temperatures. This method ensures complete destruction of heat-resistant microorganisms.
UV Radiation: UV radiation can be used as a non-chemical method to disinfect water by damaging the DNA of microorganisms.
Hot Water Circulation Loop and Its Temperature:
The hot water circulation loop is an integral part of the sanitization process in pharmaceutical water systems. It involves circulating hot water throughout the system to ensure uniform distribution of heat and effective sanitization. The temperature of the hot water loop is typically maintained between 80°C to 85°C (176°F to 185°F).
Significance of Maintaining Hot Water Loop Temperature:
Maintaining the specified temperature in the hot water loop is critical for several reasons:
Microbial Elimination: Higher temperatures ensure the destruction of a wide range of microorganisms, including bacteria and most heat-sensitive fungi.
Effective Sanitization: The prescribed temperature and duration of hot water circulation guarantee effective sanitization of the entire system, including dead legs and hard-to-reach areas.
Prevention of Biofilm Formation: Adequate temperature helps prevent the formation of biofilms, which are communities of microorganisms that can be resistant to sanitization.
Regulatory Compliance: Regulatory authorities often specify the temperature and duration for hot water sanitization in pharmaceutical water systems, and maintaining these parameters ensures compliance with industry standards.
Principle of Working of Reverse Osmosis, Ion Exchange Resins, and Activated Charcoal in Pharmaceutical Water Systems
1. Reverse Osmosis (RO):
Working Principle:
Reverse Osmosis is a membrane-based filtration process that removes a wide range of impurities from water by applying pressure to force the water molecules through a semi-permeable membrane. The membrane has very fine pores that allow only water molecules to pass through, while rejecting dissolved salts, ions, organic compounds, and other contaminants.
Applications in Pharmaceutical Water Systems:
RO is commonly used as the initial purification step in pharmaceutical water systems toremove large particles, dissolved solids, and other contaminants from the feedwater. It significantly reduces the total dissolved solids (TDS) and hardness, providing a clean and reliable source for subsequent purification stages.
2. Ion Exchange Resins:
Working Principle:
Ion exchange resins are porous, bead-like materials with functional groups that attract and exchange ions. In a water purification context, there are two types of ion exchange resins: cation exchange resins and anion exchange resins. Cation exchange resins attract and remove positively charged ions, such as calcium, magnesium, and sodium, while anion exchange resins remove negatively charged ions like chloride, sulfate, and nitrate.
Applications in Pharmaceutical Water Systems:
Ion exchange resins are used to achieve specific water quality goals in pharmaceutical water systems. Cation exchange resins can soften water by removing hardness-causing ions, while anion exchange resins can help reduce conductivity and remove specific anions that may be undesirable in the final product.
3. Activated Charcoal:
Working Principle:
Activated charcoal, also known as activated carbon, is a highly porous material with a large surface area. The process of activation involves heating the charcoal to create pores and crevices that increase its adsorption capacity. It works by adsorbing organic compounds, chlorine, and some volatile substances present in the water.
Applications in Pharmaceutical Water Systems:
Activated charcoal is used in the water purification process. It effectively removes trace amounts of organic impurities, chlorine, and certain taste and odor-causing substances, ensuring the water’s high purity and clarity.
Use in Pharmaceutical Water Systems:
The combination of Reverse Osmosis, Ion Exchange Resins, and Activated Charcoal provides a comprehensive approach to pharmaceutical water purification:
Pretreatment with Reverse Osmosis: The RO process removes large particles, dissolved solids, and other contaminants, setting the stage for further purification.
Ion Exchange Resins for Specific Purity Goals: Cation and anion exchange resins help achieve specific water quality targets by removing ions that could impact the final product’s quality.
Activated Charcoal Polishing: The activated charcoal column ensures the water is free from organic impurities and chlorine, resulting in ultrapure water suitable for critical pharmaceutical applications.
Valves Used in Pharma Water Systems:
Diaphragm Valves: Diaphragm valves are widely used in pharma water systems due to their excellent sealing capabilities and ease of cleaning. The diaphragm creates a barrier between the process fluid and the environment, preventing any leaks or contamination. They are particularly useful in applications requiring precise control of flow.
Valves Not Used in Pharma Water Systems:
Gate Valves: Gate valves are generally not preferred in pharma water systems due to their design, which can trap particles and lead to contamination. Additionally, they are slower to operate and may not provide the level of flow control necessary in pharmaceutical processes.
Globe Valves: Globe valves, although commonly used in various industries, are not the best choice for pharma water systems. Their design can cause pressure drops and turbulence, increasing the risk of contamination.
Ball Valves : As in case of ball valves a cavity holds small amout of water when it is in closed position therefore ball valves should not be used in pharma water system as this stagnant water may grow microorganisms and can become a source of microbial contamination.
Pharma Water System Conductivity Measuring Devices:
To ensure the quality of water in pharmaceutical processes, conductivity measuring devices play a crucial role. These instruments determine the electrical conductivity of water, which indicates its purity and ability to conduct electrical currents. Low conductivity signifies high purity, while elevated conductivity levels could indicate the presence of contaminants.
1. Conductivity Probes: These are simple and widely used devices for measuring the electrical conductivity of water. They consist of two or more electrodes immersed in the water, and the conductivity is measured based on the electrical resistance encountered.
2. Inline Conductivity Sensors: Inline conductivity sensors are integrated into the pharma water system’s piping, allowing real-time monitoring of water conductivity as it flows through the system. These sensors provide continuous data, enabling immediate response in case of any fluctuations in water quality.
Flow Meter for Pharma Water System: Principle of Working:
Flow meters in pharma water systems are crucial for accurately measuring and controlling the flow rate of water during various processes. The principle of working varies depending on the type of flow meter used. One commonly used flow meter principle in the pharmaceutical industry is the “Magnetic Flow Meter.”
Magnetic Flow Meter Principle of Working:
The magnetic flow meter, also known as a magmeter, operates based on Faraday’s law of electromagnetic induction. The key components of a magnetic flow meter include a non-conductive pipe liner, electrodes, and a magnetic field generator. When water flows through the pipe, it comes into contact with the electrodes. Simultaneously, a magnetic field is applied perpendicular to the flow direction.
As water, a conductive fluid, moves through the magnetic field, it generates a voltage proportional to its flow velocity. The electrodes pick up this voltage, and the flow meter’s electronics convert it into a flow rate reading. The absence of moving parts in the magmeter makes it ideal for pharmaceutical applications since it reduces the risk of contamination and minimizes maintenance requirements.
Microbial Limits in Purified Water
Microbial contamination in pharmaceutical waters poses a significant risk, as it can compromise the quality and efficacy of drugs. Therefore, it is crucial to monitor and control the microbial load in purified water. According to the USP, purified water must meet microbial limits to be considered suitable for pharmaceutical use.
The USP specifies the microbial enumeration test (the total viable aerobic count) to determine the microbial load in purified water. The microbial limits vary depending on the intended use of the water. For example, purified water used in non-sterile pharmaceutical preparations must not exceed 100 colony-forming units (CFU) per milliliter, whereas purified water used in sterile preparations should not contain any detectable CFUs.
Stem Sampling Points
Stem sampling points are strategically located points in the water distribution system that allow for representative sampling of the water quality. These points are critical in assessing the overall microbial and chemical quality of the water throughout the pharmaceutical manufacturing process. Regular sampling at these points ensures that any potential issues are detected early, and corrective actions can be taken promptly.
The selection of stem sampling points is carefully planned to cover all critical areas of the water system, including points that are vulnerable to contamination or those that can affect the quality of the final product. The samples collected at these points are tested for microbial load and other quality parameters as per USP guidelines.
Conductivity and Action/Alert Limits
Conductivity is an important parameter that helps assess the purity of water. It measures the ability of water to conduct an electrical current and indirectly indicates the presence of ionic impurities. Conductivity is generally measured in microsiemens per centimeter (µS/cm) or microsiemens per centimeter at 25 degrees Celsius (µS/cm @ 25°C).
USP guidelines set specific action and alert limits for conductivity. These limits are essential in ensuring that any deviation from the desired conductivity range is promptly addressed. The action limit indicates the point at which immediate investigation and corrective action are required to identify and rectify the issue. The alert limit serves as an early warning, allowing proactive measures to prevent the system from reaching the action limit.
Deviation from established conductivity limits could indicate problems with the water purification system, such as resin exhaustion, microbial contamination, or improper maintenance. By closely monitoring conductivity and adhering to action and alert limits, pharmaceutical companies can maintain the purity of water used in their processes.
Action and Alert Limits for Conductivity
Action and alert limits for conductivity are set to promptly detect deviations from the desired conductivity range. These limits act as early warning indicators, allowing pharmaceutical companies to take proactive measures before the system reaches a critical state.
The specific action and alert limit values may vary depending on the type of pharmaceutical water being used and the intended applications. For instance, purified water used in non-sterile pharmaceutical preparations typically has different limits compared to water used in sterile applications.
As an example, let’s consider a pharmaceutical purified water system for non-sterile preparations:
Action Limit: If the conductivity value exceeds the action limit, it indicates a potential issue with the water purification system or a contamination event. At this point, immediate investigation and corrective actions are required to identify and rectify the problem. The action limit is typically set to a value that signifies a significant deviation from the acceptable conductivity range.
Alert Limit: The alert limit serves as an early warning sign that the system is approaching the action limit. When the conductivity value reaches the alert limit, proactive measures should be taken to prevent the system from exceeding the action limit. The alert limit is typically set at a value that indicates a moderate deviation from the desired conductivity range.
Microbial Count in Pharmaceutical Water
Microbial contamination in pharmaceutical water can lead to serious consequences, including compromised product quality and potential health risks to patients. Therefore, monitoring and controlling the microbial count are essential to maintaining the purity of pharmaceutical waters.
Action and Alert Limits for Microbial Count
The USP specifies the microbial enumeration test to determine the microbial count in pharmaceutical purified water systems. The action and alert limits for microbial count are based on the USP guidelines and the specific application of the water.
For example:
Action Limit: If the microbial count exceeds the action limit, it indicates that the water may not be suitable for its intended use due to a high level of microbial contamination. Immediate investigation and corrective actions are necessary to address the issue and prevent further contamination.
Alert Limit: The alert limit indicates a potential upward trend in microbial counts. When the microbial count approaches the alert limit, proactive measures should be taken to investigate and mitigate any potential sources of contamination before it exceeds the action limit.
The United States Pharmacopeia (USP) has established specific limit values for bacterial count, fungal count, and conductivity in pharmaceutical water or purified water to ensure its quality and safety. These limits vary depending on the intended use of the water and the specific USP monograph being followed. Below are the general limit values for each parameter:
Bacterial Count:
Purified Water (used in non-sterile pharmaceutical preparations):
Action Limit: NMT (Not More Than) 100 colony-forming units (CFUs) per milliliter.
Alert Limit: NMT 50 CFUs per milliliter.
Water for Injection (used in sterile pharmaceutical preparations):
Action Limit: No specific CFU limit. Water for Injection should not contain any detectable CFUs.
Alert Limit: No specific CFU limit. It should not exhibit an upward trend in microbial counts.
Fungal Count:
Purified Water (used in non-sterile pharmaceutical preparations):
Action Limit: NMT 10 CFUs per milliliter.
Alert Limit: NMT 5 CFUs per milliliter.
Water for Injection (used in sterile pharmaceutical preparations):
Action Limit: No specific CFU limit. Water for Injection should not contain any detectable CFUs.
Alert Limit: No specific CFU limit. It should not exhibit an upward trend in fungal counts.
Conductivity:
Purified Water (used in non-sterile and sterile pharmaceutical preparations):
Action Limit: NMT 2.1 µS/cm at 25°C.
Alert Limit: NMT 1.5 µS/cm at 25°C.
Water for Injection (used in sterile pharmaceutical preparations):
Action Limit: NMT 1.3 µS/cm at 25°C.
Alert Limit: NMT 1.0 µS/cm at 25°C.
Referances: https://www.fda.gov/