Missing an excursion in your water purity system can cause costly and time-consuming problems downstream. That's why the USP <645> standard exists—it's the lifeline of water quality in drug production. This gold standard sets the bar high, ensuring every batch of medication flowing through manufacturing meets the highest quality standards.
But achieving USP <645> compliance isn't simply a matter of following a checklist. It's about having a reliable partner in your corner. Enter real-time conductivity monitoring. Think of it as your secret weapon, offering a constant pulse on your water's health. Any potential contaminants attempting to infiltrate your system? Real-time monitoring catches them before they wreak havoc.
The United States Pharmacopeia (USP) <645> standard serves as a globally recognized benchmark for ensuring the purity of water used in pharmaceutical manufacturing. This vital document serves a two-fold purpose:
The meticulous regulations of USP <645> lay out comprehensive test methods that must be met to determine the inorganic/ionic impurities of PW, WFI and pure steam condensate. USP <645> is a three-stage test method for on-line or off-line water conductivity testing. By adhering to these strict standards, the integrity and efficacy of life-saving medications are safeguarded.
In addition to defining quality parameters, USP <645> also mandates rigorous testing procedures for pharmaceutical companies. The testing process involves a three-stage conductivity measurement, among other measures, to ensure that all water samples meet the established standards.
Stage 1: This stage is intended for on-line measurement and involves measuring the on-line temperature and non-temperature-compensated conductivity of the water at the test measurement reporting point to ensure the conductivity is below specified limits in the monograph.
Stages 2 and 3 are for off-line testing.
Stage 2: This stage requires taking a sample and stirring it to equilibrate to atmospheric CO2. If the conductivity is less than 2.1 μS/cm at 25°C ± 1°C, it passes. If not, move to Stage 3.
Stage 3: Saturate the sample from Stage 2 with potassium chloride (KCl). Measure pH to the nearest 0.1 pH unit. Look up the conductivity limit for that pH in Table 2 in USP <645> or in the table below. If the measured conductivity (from Stage 2) is less than the conductivity limit, it passes. If the measured conductivity is greater than this value or the pH is outside the range of 5.0 – 7.0, the water does not meet the requirements of USP <645> for conductivity.
By following the three-stage test method, pharmaceutical companies can ensure the quality of their water and, ultimately, the safety and effectiveness of their drugs.
The three-stage conductivity testing outlined in USP <645> is a critical safeguard for water purity. It's important to remember, however, that Stage 1 is intended for on-line testing. No further testing is required if a water sample passes the conductivity limits in Stage 1, hence the advantage of on-line conductivity measurement.
Unlike on-line conductivity measurement, off-line testing requires implementing Stages 2 and 3 to ensure that the conductivity measurement is within acceptable limits. Here's where real-time (on-line) conductivity monitoring offers significant advantages over relying solely on off-line testing, particularly for Stage 2:
In essence, on-line, real-time conductivity monitoring reduces the three-stage test method to just Stage 1, saving time and providing confidence in water quality. Real-time monitoring empowers pharmaceutical companies to achieve and maintain the highest standards of water quality by providing continuous monitoring, improved process control, and a reduced risk of non-compliant batches.
Despite the robust framework provided by the three-stage conductivity testing mandated in USP <645>, achieving consistent compliance can still be a persistent challenge for pharmaceutical companies when they rely solely on traditional testing methods. Let's explore some of the common hurdles that traditional methods present:
Traditional USP <645> testing methods, while valuable, can leave pharmaceutical companies vulnerable to gaps in their water quality monitoring. Fortunately, real-time conductivity monitoring offers a significant enhancement to traditional USP <645> testing methods, providing pharmaceutical companies with more comprehensive and proactive water quality management.
Unlike grab samples that offer a single snapshot in time, real-time monitoring provides a continuous stream of data. This allows for the early detection of even minor fluctuations in conductivity, potentially indicating the presence of contaminants before they significantly impact water quality. With real-time data at your fingertips, you can identify and address potential issues swiftly, preventing them from snowballing into bigger problems.
Real-time monitoring eliminates the time delays inherent in traditional testing methods. By providing instant alerts for out-of-specification conductivity readings, real-time monitoring empowers you to take immediate corrective action. This faster response time minimizes the risk of contamination spreading and safeguards subsequent batches of water from being compromised.
Real-time conductivity monitoring goes beyond simply identifying deviations. The continuous data stream it generates allows for a more proactive approach to water quality management. By constantly monitoring conductivity trends, you can gain valuable insights into the performance of your purification system. This empowers you to make adjustments and optimize the system as needed, ensuring consistent water quality throughout the entire production process.
In short, real-time conductivity monitoring transforms water quality management from a reactive to a proactive endeavor. By providing continuous data for early detection, faster response times, and improved process control, real-time monitoring empowers you to achieve and maintain USP <645> compliance with greater confidence.
Accurate Calibration: Enhanced Water Quality Management
While traditional USP <645> testing methods provide valuable insights, accurate calibration can significantly enhance your water quality management. Through precise calibration, you can be confident that your instrument meets exact standards, offering reliable data for informed decision-making. Without proper calibration, even the most advanced real-time monitoring system could provide misleading information, putting your compliance efforts at risk.
Proper Measurement Techniques: Following the USP <645> Blueprint
Beyond instrument calibration, proper measurement techniques are crucial for obtaining the precise conductivity readings necessary for USP <645> compliance. Following the guidelines outlined in the standard, such as maintaining proper sample temperature control and adhering to cell cleaning procedures, is vital for maintaining data integrity. In essence, meticulous adherence to these best practices ensures your real-time conductivity monitoring system functions at its peak, delivering the accurate measurements you need.
Keeping up with USP <645> compliance is an ongoing priority for pharmaceutical companies. While traditional testing methods are important, they can cause delays and restrict your proactive management of water quality. Real-time conductivity monitoring is a game-changer, providing you with the tools to truly comprehend the purity of your water at every stage of production. By offering continuous data for early issue detection, quicker response times for necessary actions, and enhanced process control, real-time monitoring enables you to guarantee consistent water quality, maintain rock-solid USP <645> compliance, and ensure a smooth and reliable production process.
This ultimately translates to peace of mind, knowing that your pharmaceutical products are manufactured with water that meets the most stringent purity standards.
METTLER TOLEDO understands the critical role water purity plays in pharmaceutical manufacturing. That's why we offer a range of industry-leading conductivity analyzers specifically designed to meet the rigorous demands of USP <645> compliance. Our instruments offer exceptional accuracy, seamless integration with existing systems, and real-time data visualization tools. They empower you to make data-driven decisions and ensure the consistent purity of your pharmaceutical water.
Partner with METTLER TOLEDO today and experience the real-time advantage of guaranteed water purity and unwavering USP <645> compliance. Let our expertise guide you towards achieving the highest standards in pharmaceutical water quality.
In this white paper, you will find a comprehensive overview of USP <645> water conductivity regulations, detailing the three-stage testing method, calibration requirements, and the advantages of on-line measurement, alongside insights from METTLER TOLEDO solutions.
Global Pharmaceutical Segment Specialist
Areen Kalantari holds a B.S. in Biological/Chemical Engineering and a Master of Business Administration (MBA) in International Business. He has experience in both biotechnology applications and pharmaceutical waters. Areen has previously worked as a pH, dissolved oxygen, and CO2 product manager, working with global pharmaceutical and biotech customers to implement effective SOPs and to train personnel for their cell culture and fermentation processes. Areen is a voting member of the American Society of Mechanical Engineers – Bioprocess Equipment (ASME-BPE) standards committee. He contributes to the Process Instrumentation subgroup to help implement standards for the bioprocessing and pharmaceutical industries, focusing on conductivity, pH, TOC, and various other process technologies. In his current role, he supports the global market for pharmaceutical water systems and USP regulatory aspects of WFI and PW systems regarding required tests to be conducted.
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USP <645> is a test chapter within the United States Pharmacopeia that outlines a three-stage test method for determining the quality of Purified Water (PW), Water for Injection (WFI), and condensate of Pure Steam for pharmaceutical application. While USP is harmonized with most other global pharmacopeias, in order to sell pharmaceutical products, cosmetics, dental products, and others into the U.S. market, water used to manufacture those products must meet the conductivity requirements set forth in USP <645>.
In addition to outlining a test method for PW, WFI, and condensate of Pure Steam, USP <645> also specifies accuracy and calibration requirements for the instrumentation used to make compendial measurements.
Regarding instrument capability:
Regarding instrument calibration:
If a conductivity measurement instrument does not meet even one of these requirements, it is not a compliant solution.
Yes, a conductivity sensor can provide uncompensated conductivity and temperature measurements simultaneously. While it is acceptable to measure conductivity and temperature on two different instruments, getting both measurements simultaneously from one conductivity sensor can significantly reduce cost and complexity. Some direct integration solutions may not have the necessary outputs to provide both measurements at the same time.
Most device manufacturers offer the ability to calibrate sensor cell constant and temperature measurements either in the field or with factory support. However, the vast majority do not provide a clear methodology for performing the measurement electronics calibration specified in USP <645>.
Many sensors available on the market either need to be calibrated on a lab bench or sent back to the manufacturer for calibration. This requires you to shut down and break into your validated water system introducing contamination risk and potentially requiring re-validation.
Solutions that allow compliant calibration without removing the sensor from process significantly reduce associated cost and headaches.
METTLER TOLEDO's UniCond sensors stand out as the only conductivity sensors on the market that can be calibrated in full compliance with USP <645> standards without needing to remove them from your validated water system.
To ensure accurate and reliable conductivity measurements, it's essential to select a conductivity sensor that meets or exceeds the rigorous standards outlined in USP <645>. A crucial initial step is to verify that a device adheres to the accuracy and resolution standards outlined in USP <645>.
METTLER TOLEDO provides a comprehensive range of conductivity measurement solutions, including:
UniCond conductivity sensors contain both the electrode and the measurement circuit in a single, compact unit. This enhanced design enables a wide measurement range as well as accuracy and precision on both conductivity and temperature measurements that exceed USP <645> requirements.
METTLER TOLEDO M800, M300, and M200 transmitters allow you to measure uncompensated and compensated conductivity along with temperature simultaneously, allowing you to satisfy compendial measurement requirements while also controlling your process from the same measurement point.
State-of-the-art technology combined with METTLER TOLEDO’s expert service make the UniCond the only conductivity sensor available today, with the ability to be calibrated in full compliance with USP <645> requirements without removing the sensor from your validated water system.
