The article talks about implementing automated online TOC analyses at different points of use, comparing it to off-line laboratory TOC analysis techniques in terms of cost, setup, implementation and operation. The article stresses on controlling the TOC quality attribute for the release of PW and WFI for product manufacturing processes. It also talks about effective regulatory compliance and validation, as well as effective management of water system. It talks separately about the issue of the TOC instrument, its response efficiency and system suitability and acceptability tests, as well as the water test in terms in light of the current USP, EP regulations. It then talks about implementing PAT initiatives with the use of sensors to automate release of water for the online TOC analysis, discussing different configurations & setups.
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Currently in industry, the use of offline laboratory TOC analyzers is much more common as compared to online TOC analyzers. The industry feels no need to improve on existing systems or processes. Companies tend to focus on quick and easy validation rather than effective validation. Lab TOC analyzers are used for fulfilling regulatory requirements, QC approval of water TOC attribute. They are good for fulfilling USP and EP regulations, for dealing with many water loops, and for cleaning validation too. As companies are required to determine bacteria, endotoxins for different water use points by default, TOC samples have to be collected & analyzed with laboratory TOC analyzers. At times, it is even difficult to do the System Suitability Test on online TOC analyzers for quality assurance demonstrating acceptable TOC analysis. The initial capital cost for implementing automated online TOC system for water release can be expensive, and if the system is not well understood, that can cause a lot of additional problems and expenses. These are some of the reasons why many companies refuse to convert to on-line TOC analysis for water release. For passing the TOC attribute test to send the water for manufacturing processes, both the water being tested and the analyzer suitability, acceptability criteria must be fulfilled.
The System Suitability Testing is not explained by USP or EP. The System Suitability testing frequency is determined by user, and the factors for determining it are the water used between SS testing, costs of SS testing, reliability of analyzer to pass the test and internal risk assessment of product produced. The suitability of TOC Analyzers is determined by three solutions: a blank, sucrose at 0.5mg.C/L and 1,4 benzoquinone at 0.5mg.C/L. Using these pieces of information, the response efficiency can be calculated. If the TOC analyzer response is greater than 85% and less than 115%, the analyzer has passed the test. The regulatory requirements for the water to pass are if its concentration is less than the concentration of sucrose subtracted from the blank. The system suitability test compares the “recovery” of the analyzer for an easy-to-oxidize sucrose and a hard-to-oxidize (1,4 benzoquinone) standard. The relationship of the independent recoveries must be periodically demonstrated and fall within specified limits.3 In addition to the required system suitability test, an on-line instrument will require periodic calibration and verification.
For acceptable water test results acceptability, so it can be sent for the manufacturing processes; the suitability and acceptability of the analyzer must be demonstrated both before (initial suitability test) and after water testing (final suitability test). This is where a lot of failures can occur in both the offline and online TOC analyzer systems. But in the case of online TOC analyzer systems, once the process and its sources of variations are understood properly, there is a very minimal chance that the system suitability tests will fail.
Some of the advantages automated on-line TOC analysis systems have over off-line laboratory TOC analysis systems are elimination of manual sampling errors. Sampling is the area where most errors take place in Analysis. TOC analyses before sending the water for manufacturing processes is extremely sensitive. It is imperative to have extremely accurate analysis for the measurements of TOC in the water, as it will have a huge impact on the processes since water is used everywhere in the form of critical utilities. It is important that there are essentially no inaccuracies in its measurements. The on-line TOC analysis if implemented correctly can do that, but an off-line laboratory TOC analyzer cannot. The other advantage that an on-line TOC analyzer has over an off-line is that it results in process automation, which results in less utilization of company resources that can be deployed elsewhere, as well as decreasing the operating costs. Online analyzers are also better for repetitive, routine TOC testing requirements.
In the past, pharmaceutical companies used to rely on lab TOC analyzers to meet USP, EP or JP requirements for PW and WFI release. However, by implementing an approach centered round the use of PAT initiatives, as well as a real-time release program using an on-line TOC analyzer, companies are realizing the benefits of reduced cost, reduced waste and improved consistency of quality production. On-line TOC analyzers allow re-focusing of lab resources to other more critical quality control and product development activities, while maintaining better regulatory compliance
The critical factors for implementing on-line TOC are regulatory expectations, reliability, analytical performance, ease of use and elimination of manual errors.
By using online TOC analyzers instead of offline laboratory TOC analyzers, we are removing the most common source of error in chemical analysis, which greatly helps us increase the analytical performance of the online TOC analyzer, increase the ease of use, and eliminate manual errors from the system. By using a dual (2) on-line analyzers in a single loop, we are increasing the robustness and reliability of the online TOC analysis system. Payback on investment is also achieved in 1 year’s time. This is discussed later in the paper in more depth.
To understand how to implement the automated online TOC analyzer system for the release of water successfully and effectively, we have to understand the sources of variation for TOC quality attributes, as well the critical parameters and quality attributes, the manufacturing process itself, and learn how to control all of these as well as the in-process water coming from the source raw water feed.
This fits in perfectly with the PAT initiative that quality must be built into a system or a process rather than tested into it, as well as understanding and effectively controlling the process, by analyzing and controlling it through timely measurements of critical quality and performance attributes of its source feeds. All of this will lead to a better controlled, effective and optimized design of the system or process, and this will in turn result in the superior products. If one takes out ‘drug product’ and ‘raw materials’ from the context of the definition of the PAT and replaces it with water (PW or WFI), the idea of PAT can be used to on effectively implementing an automated online TOC analysis system that will result in the same advantages. Using the PAT initiatives for automated online TOC analysis for water release can also greatly help in the regulatory requirements that need to be fulfilled as well.
The concept of PAT also encourages scientific, risk-managed pharmaceutical development, quality assurance. Less rejects, reprocessing improves the efficiency of the process, which in turn increases capacity. As WFI water is extremely expensive and is the most common excipient, and ingredient in drug manufacturing; the company must make sure that not a lot of it is rejected before the manufacturing process and/or wasted, and/or is reprocessed instead of being wasted. This also perfectly aligns to the PAT initiatives.
The PAT concept encourages the company to manage variability instead of rejecting it. Some of the sources of variability in online TOC analysis systems are: a) source water or raw water feed. This has a huge effect on the final TOC. b) PW & WFI storage tanks c) Distillation units: PW is supplied to it to produce WFI. TOC can leak into WFI if main distillation unit develops heat exchanger leak depending on TOC quality.
The PAT requirements for water release system are understanding of TOC or conductivity removal/addition processes and the sources of conductivity/TOC. The determination of critical TOC and conductivity control points, implementation of TOC and conductivity analyzers, as well as requirements for the control system is part of the PAT initiative. There also needs to be a control element (manual or automatic) for water release.
In implementing the PAT initiative, the component of real time release includes assessed material attributes and process controls. Combined process measurements and test data gathered during manufacturing process is used for real time release for final release of product, and this demonstrates compliance with regulatory quality attributes.
Online TOCs analyzers measure TOC representing a specific point of use. So the acceptability of on-line TOC analyzers for TOC attributes testing depends on its location in system. Instrument responses at a point of locations should reflect quality of water used at that point. For on-line TOC analyzers, the value of TOC with released water depends on the time interval between consecutive SS Tests. SS tests should take place continually as long time intervals between consecutive SS tests results in failure (Out of Specification results).
The online TOC analyzers can be set up in different ways and configurations for testing the water TOC. It is important to set up the equipment correctly and calibrate it, because it is part of the Installation Qualification (IQ). If the IQ is not done correctly, it will result in the failing of the System Suitability test and acceptability test for water and/or on-line analyzer, which means a failed Operational Qualification (OQ). Equipment can be installed and operational, but the final steps to release the water to production may not be implemented. This results in the failure of the Performance Qualification (PQ) for that system, because the wrong IQ and OQ took place.
The cheapest way for an online TOC analysis is using a single online TOC analyzer on the exit of the distribution loop just before return to the storage tank, and the laboratory TOC analyzer is the backup to the online TOC system. Unfortunately, this method is also the least robust, because if this one online TOC analyzer does not pass the system suitability test, the process will lose its automation. However, if the same analytical measuring technology is used for both analyzers, the potential instrument response variances between the two analyzers is eliminated, which means the off-line laboratory TOC analyzer can be used to determine at which point of use the online TOC analyzer went wrong, by comparing the TOC analysis values of the online and offline TOC analyzers. Comparing the two readings from the analyzer can also be used to fulfill the Performance Qualification (PQ) requirements. But this would require very frequent sampling on the lab TOC analyzer, & there is a chance that the exact point and time of failure, where the on-line TOC failed the SS test cannot be determined effectively.
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The most robust and reliable method is using dual on-line TOC analysis system. To achieve this kind of setup, two on-line TOC analyzers must be installed onto a single distribution loop. If one of the TOC fails the SS test when it is releasing the water; and if it can be proven that the 2 TOC analyzers on the distribution line are measuring the same water: the other TOC analyzer will serve as a backup and make sure that the TOC analysis and the release of the water is still automated. There is very less likelihood that both TOC analyzers fail the SS test at the same time. A laboratory off-line TOC can also be used again for PQ purposes. But it is imperative that both the analyzers are measuring the same water and its TOC for one to be used as a backup for the other. If it is not, there is a chance that “unacceptable” is being released for manufacturing processes.
As mentioned in the paper before, as the testing of its TOC critical attributes depends on the point of use, the TOC(s) can be used in any kind of arrangement to serve different purposes, such as ensure the various components in the loop (such as the Distillation or other water purification systems) are working correctly or not. The diagram below the PW feed going into the line, and the WFI feed coming out from the distillation unit. One TOC analyzer is connected to the PW feed line, the other one is connected to the WFI feed line. Comparing the readings from both these TOC analyzers can tell whether the distillation unit is working correctly or not. There might be a risk that the distillation unit or distribution loop is adding TOC to the water as a result of system failure, which means that the backup TOC is not fulfilling its purpose.
The whole point of using an on-line TOC analysis system over an off-line lab TOC analyzer is for the purpose of the recirculation of the PW or WFI. If the water is needed for a specific point of use in an off-line lab analyzer, the water will be manually taken and sampled on the off-line TOC analyzer. If that sample fails, essentially the whole stream of water most probably fails too. If the off-line lab analyzer fails or the water test fails, all that water which is very expensive will go to waste, and will not be recirculated. In the online TOC analyzer system, once it has been figured out where (at which point[s] of use, if it is being added) TOC is being added to the water; that is remedied. When that has been resolved, all the sources of variability have been identified; all the components are installed and functioning correctly, the water can be recirculated over and over, making this a continuous automated process. The storage tank will always be filled because when the water is being distributed from the storage tank to various points of use, the WFI feed coming out the distillation unit will always be filling up the lost water.
Implementing the PAT initiative into the automated online TOC analysis also means implementation of automated real time TOC release systems, computer, data acquisition, process sensors, process equipment & process analytical instrumentation integrated into a comprehensive management system. The comprehensive management system ensures continual operation process within prescribed limits to ensure quality. Supervisory Control and Data Acquisition Systems (SCADA), distributed control systems (DCS), Facility Monitoring Systems (FMS), Programmable Logic Controllers (PLCs) and Man-Machine Interfaces (MMI) are other tools that can be used as well. PAT guidance documents aid operation, control, monitoring water systems integrating automation, sensory data, & feedback mechanisms with target to implement PAT & online instrumentation for automatic formal QC water release to production.
Proven technology allows for the automation of standards introduction and data management. Radio Frequency Identification (RFID) is one such technology, and standards can be loaded into the TOC analyzer and processed automatically to produce results. The figure below shows an automated standards introduction system in an on-line TOC analyzer:
RFID is a well known technology that is currently used in the pharmaceutical industry as a preventative measure against counterfeiting. It uses an RFID tag that comprises of a microchip, substrate and an antenna) and a reader/writer. The RFID tag is programmed with all the data related to a specific standard, including the contents of the bottle, certified concentration, lot number and expiration date.
Once the RFID tag aligns with the reader/writer, the data is automatically transferred to the analyzer. There is no need for any manual input here. The only thing someone has to do is simplified through an easy to use and understand touch-screen man-machine interface (MMI)
Problems can arise in online TOC analysis system if contaminants enter the water systems that are harmful for the system operating. Even though current water system technology produces very consistent and reliable results, excursions can occur. Excursions are discrepancies from normal water system operating conditions. When an excursion occurs, that means that quality of water produced is questionable. If there is excursion in the system, it is a good idea to obtain a sample of water from the system on which an independent analysis can be done. Analysis of the water sample can provide information about why the excursion occurred, and that would help in rectifying the problem of excursion.
Some TOC analyzers use methods to separate compounds that are not expected to come in contact with process water from the analysis. Reverse osmosis (RO) membranes are susceptible to damage from chorines and chloramine by-products in disinfection process. If chlorine or any of its biproducts cracks into the water system or even has a small presence of it; that means that the system has failed. If a TOC analyzer is designed to separate these compounds from the analysis, it will only hide the problem and will not rectify it in any way. TOC analyzers designed to respond to contamination by the presence of these compounds in the process water, by capturing a sample of water; but only if that sample is equipped with excursion monitoring capability. This helps the water system engineer to identify the problem and rectify it. A TOC analyzer equipped with an OASISâ„¢ may be configured for excursion monitoring. Excursion monitoring is defined as the ability to extract and save a sample of water from process water right after a pre-programmed water condition such as such as high TOC levels, water conductivity with regard to USP limits, water chemistries deemed wrong by analyzer and his analysis, have been implemented.
Using this technology, problems with process water can be identified well before limits have been exceeded, with ability to program a specific TOC level that must be exceeded for excursion capture. In case of the identification of an excursion in the process water, the analyzer will immediately capture a sample of water directly from the water system and place it in an empty bottle, equipped with an RFID tag that has been loaded into the analyzer. Upon sample capture, all the data associated with the excursion is recorded on the RFID tag using the writing capability of the RFID reader/writer. The integration of the RFID with excursion monitoring enables that the data associated with captured excursion water is protected and cannot be changed. A lab equipped with the appropriate RFID reading capability, has the ability to read the tag and associate the data with the water sample, such as the serial number of the analyzer, date, time, last TOC, conductivity and temperature values. Because of this type of analysis for the process water, better understanding for the reasons for the cause of the excursion can be identified. As the excursion capture is initiated by the TOC analyzer results, the sample is as indicative of the water condition as possible.
The PAT enables application of risk-based approaches to enhance quality of a process. By applying excursion monitoring capability, risks associated with producing off-spec water is greatly reduced. The TOC analyzer becomes a water system diagnostic tool, rather than just a regulatory sensor to monitor TOC limits.
In the past, pharmaceutical companies used to rely on lab TOC analyzers to meet USP, EP or JP requirements for PW and WFI release. However, by implementing an approach centered round the use of PAT initiatives, as well as a real-time release program using an on-line TOC analyzer, companies are realizing the benefits of reduced cost, reduced waste and improved consistency of quality production. On-line TOC analyzers allow re-focusing of lab resources to other more critical quality control and product development activities, while maintaining better regulatory compliance. This conversion of approach from a simple reproduction to a more risk based approach which reduces variability (instead of rejecting it) enables the implementation of new technologies and more cost effective measures, which in turn results in more efficient and effective processes and higher quality products. With the advent of the Process Analytical Technology (PAT) & Quality by Design (QbD) approaches, the desire is to evolve pharmaceutical processes from an art to a science with engineering-based activity, application of enhanced science and engineering knowledge in regulatory decision-making, establishment of specifications and evolution of manufacturing processes. With the advent of new technologies such as RFID and MMI, the automated process has been simplified, been made more effective. With excursion monitoring, a TOC analyzer becomes more than just a TOC sensor for regulatory purposes. It becomes a tool that minimizes the risk of falling out of specification. Implementing new technologies through PAT allows the addition of true value wherever traditional regulatory compliance is required.
I believe there is a lot to be learned and implemented on this topic in industry. I found the topic highly important and of high learning. I hope to work in a pharmaceutical company that can implement such initiatives in water systems.
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