Real-time total organic carbon (TOC) and conductivity testing enables optimized monitoring programs for pharmaceutical grade water systems. With online monitoring, manufacturers achieve better process control, efficiency gains, and risk management for CGMP processes.
Benefits of Real-time TOC Testing
- Reduce or eliminate costs, resources, contamination, laboratory errors, and delays in data associated with traditional grab sampling.
- Detect and remediate out-of-specification (OOS) or out-of-trend (OOT) results in real time.
- Demonstrate a continuous state of control and system validation.
- Document and predict trends, and use data to establish alert and action levels for a given system.
- Use total organic carbon, inorganic carbon, and conductivity data together for root cause analysis.
- Embrace US FDA Process Analytical Technology (PAT) Guidance for quality and efficiency gains.
- Leverage like-for-like TOC membrane technology to move from laboratory methodology to online technology.
The pharmaceutical industry demands lean processes and continuous improvement. Efficient processes allow for safe, high quality products to be available to patients when needed. The US FDA’s guidance document on Process Analytical Technology (PAT) not only describes how and when to deploy technology, it also strongly encourages manufacturers to embrace PAT within their systems. PAT gives continuous process understanding, process control, and efficiency gains to CGMP processes. When thinking about how to optimize the monitoring of pharmaceutical grade water systems, consider deploying PAT.
Total organic carbon (TOC) and conductivity monitoring are crucial aspects of purified water system quality and control. Producing TOC and conductivity data in real time using PAT ensures a controlled and understood process while saving sampling and analysis time. Pharmaceutical grade water is integral to safe and effective medicine and is often in use throughout multiple shifts of manufacturing drug product. Real-time monitoring of purified water systems ensures water in use for batches or equipment meets regulatory and internal quality requirements before, after, and at the time of use.
Process Analytical Technology (PAT)
Process Analytical Technology (PAT) guidance is a nonbinding FDA document that encourages innovation and quality in CGMP manufacturing. The key advantage of PAT is building quality into products while gaining efficiencies throughout the process. This is accomplished with robust design, reliability, risk management, and ease of use. Advantages of PAT allow for quality by design, demonstrated validation, process understanding, and process control.
Understanding and controlling a purified water system requires the ability to accurately and reliably measure quality attributes, and use the data to make important quality decisions. From there, the water purification process can be controlled and adjusted to maintain a desired, validated state. Purified water systems that demonstrate a high degree of process understanding and control provide inherent quality gains. For example, when out-of-trend (OOT) or out-of-specification (OOS) results are detected in real-time, inputs or water system characteristics can be remediated before quality suffers. When seeking ways to optimize pharmaceutical grade water systems, consider embracing PAT guidance to deploy real-time TOC and conductivity monitoring.
Real-Time TOC Data for Continuous Control and Root Cause Analysis
Total organic carbon and conductivity testing are required for pharmaceutical grade water systems used for CGMP manufacturing. These analyses are governed by USP <643> and USP <645>, respectively. Although these analyses are compulsory, they also provide valuable data to manufacturers to reduce waste and increase process efficiency, specifically when monitoring in real time with online technology. Online TOC technology, especially technology that provides total organic carbon, inorganic carbon, and conductivity data together, enables accurately predicting and understanding trends in a water system. Alert and action levels should be set based on established historical data to demonstrate the utmost control of a water system.
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While USP <643> for Total Organic Carbon is in fact a limit test, it is prudent to establish control specifications based off trending data. For example, if a water system is consistently producing 50ppb water and the online TOC analyzer starts measuring data points around 300 ppb, it is still within the USP <643> acceptance limit of 500ppb. However, this shows a deviation from the 50ppb trend. This may be within USP specification, but it is a serious red flag showing the system is out of trend and out of control. Without appropriate alert and action levels, this excursion will go undetected. Furthermore, the underlying cause of a 250ppb TOC increase from normal levels will go undetected and the root cause will be neither identified nor remediated. Setting appropriate alerts and action levels requires using validated and quantitative TOC technology.
Validation
To use PAT to its full potential, technology must be qualified, and methods must be validated per USP and ICH requirements. Without proper validation, the value of real-time data is lost. Equivalency studies/comparability protocols are needed when moving from laboratory to online, highlighting the verification and implementation approach. It is important to have a documented implementation strategy for demonstrating equivalency. From there, assess any discrepancies, if applicable. For example, perhaps results are slightly different from lab to online due to a change in temperature or the change in sample handling. Observed changes may be acceptable for the method transfer; however, these types of variances need to be acknowledged and assessed. It is important to note that some methodology transfers may be easier than others, based on the type of technology deployed. If using conductometric TOC technology in the lab, method transfer to online conductometric technology becomes simplified since they are like-for-like technology.
While the FDA encourages PAT implementation, inspectors will maintain the usual level of scrutiny and tailor it to the technology. It is important to understand what makes for compliant technology and a compliant process. PAT implementation needs to be able to withstand the same level of inspection as any other CGMP process especially when thinking about data integrity. Data integrity is not a new concept, however, as electronic records and electronic signatures have become the industry standard, there is more scrutiny on data integrity compliance. Do your TOC and conductivity data stand up to the requirements of ALCOA+ and 21 CFR Part 11? ALCOA+ is not the end all be all of data integrity, but challenging processes and data management against these principles is certainly a good place to start. Data generation and data management practices need to be clearly defined and compliant to data integrity regulations when deploying PAT.
Summary
When looking for process optimization and process improvement opportunities for CGMP water systems, Process Analytical Technology (PAT) should be considered for TOC and conductivity testing. The FDA guidance document encourages manufactures to embrace PAT in processes for quality and efficiency gains. Online TOC and conductivity monitoring gives these quality and efficiency gains while offering robust process understanding and control. Real-time data generation and release eliminates or significantly reduces sample integrity issues, quality control resources, laboratory errors, sampling costs, and delays associated with traditional laboratory analysis of purified water. Finally, improved process understanding allows for timely and detailed root cause analysis, risk identification, risk mitigation, trend analysis, and real-time detection of OOS or OOT results. There are myriad benefits of using Process Analytical Technology and Real-Time TOC Testing for Pharmaceutical Grade Water Systems.
Author Biography
Michelle Neumeyer is the Life Sciences Product Applications Specialist for the Sievers line of Analytical instruments at SUEZ – Water Technologies & Solutions. Previously, Michelle worked in Quality at Novartis and AstraZeneca, ensuring compliant water systems, test methods and instrumentation. Michelle has a B.A. from University of Colorado, Boulder in Molecular, Cellular and Developmental Biology.