Is Your Online TOC Analyzer Ready to Meet Pharmacopeia and Annex 1 Requirements?
Understanding the requirements set forth by the US and European Pharmacopeias for the analysis of Total Organic Carbon (TOC) in Purified Water (PW) and Water For Injection (WFI) is crucial for ensuring compliance and maintaining high standards in pharmaceutical water systems. Additionally, the impact of the Annex 1 on the European Union’s Good Manufacturing Practices (EU GMP Annex 1) guidelines on the monitoring of WFI systems introduces new challenges and considerations for maintaining compliance.
This webinar reviews the specific requirements of the US and European Pharmacopeias and of EU GMP Annex 1, and what they mean for TOC analysis. We explore various TOC analysis technologies and how they meet these requirements, with a focus on the advanced capabilities of the PAT700 TOC Analyzer.
This session demonstrates how the PAT700 Analyzer's innovative technology ensures seamless compliance with all relevant requirements, offering a reliable solution for your TOC analysis needs.
Learning objectives:
- Learn about the requirements of US and European Pharmacopeias for the analysis of Purified Water and Water For Injection;
- Learn about the impact of Annex 1 on WFI systems monitoring;
- Understand how the PAT700 Online TOC Analyzer helps you to comply with all these requirements.
Speaker: |
Transcript
INTRODUCTION AND AGENDA
Welcome to this webinar on online Total Organic Carbon, or TOC, analyzers, pharmacopeial requirements, and EU GMP Annex 1 requirements.
Before starting, I want to briefly show our intellectual property disclaimer, which I will let you read. I also want to mention that Beckman Coulter Life Sciences has been part of Danaher Corporation since 2011. Now, let's get started.
Today, I will first present the agenda. The first part of the webinar will focus on the regulatory environment, including an overview of the different chapters that apply to TOC analysis and pharmaceutical water. We will look in more detail at EU GMP Annex 1 requirements and European Pharmacopoeia requirements.
The second part of the webinar will focus on TOC analyzer technologies available on the market, including their advantages and drawbacks.
The final part will focus on the PAT700, the Beckman Coulter online TOC analyzer, and how it supports compliance with these requirements.
REGULATORY ENVIRONMENT
The regulatory environment for TOC analyzers comes from several different bodies. It includes the U.S. Pharmacopeia, the European Medicines Agency, or EMA, EU GMP, and the European Pharmacopoeia.
There are general chapters, such as USP <1231>, which provides guidance on water for pharmaceutical purposes. This type of general chapter provides information about the collection, validation, and testing of water used in pharmaceutical manufacturing. It covers aspects such as microbial water quality attributes and other important quality considerations.
There are also other general chapters, such as USP <643>, USP <645>, and European Pharmacopoeia chapter 2.2.44. These chapters provide more detail about total organic carbon and conductivity for water used in pharmaceutical production. They describe requirements for measuring TOC and conductivity in this type of water.
One difference between the U.S. Pharmacopeia and the European Pharmacopoeia is that USP <643> and USP <645> define both measurement requirements and water quality standards. In the European Pharmacopoeia, chapter 2.2.44 focuses on method requirements, while quality standards are defined in separate monographs, including those for purified water and water for injection.
EU GMP ANNEX 1 REQUIREMENTS
Let's now discuss EU GMP Annex 1 and the content of the revised text. The revised version was released in 2022, replacing the previous version from 2008. There are changes that directly affect how manufacturers monitor their water systems, including water for injection systems.
For example, in section 6.15, Annex 1 states that water for injection systems should include continuous monitoring for TOC and conductivity, making this type of monitoring mandatory.
If we look at the section on excursions, we also see that all local excursions should be documented and reviewed. The text also requires an investigation in the event of an excursion.
The way alert limits and action limits are defined is also pushing users toward more online analysis. Online monitoring allows users to monitor TOC and conductivity more closely and identify alert levels that provide early warning of drift. These alert levels can trigger follow-up scrutiny to address potential problems. Action limits represent a more serious deviation from normal operating conditions and should trigger immediate investigation and corrective actions.
Overall, the revised EU GMP Annex 1 places greater emphasis on the use of TOC monitoring for water for injection systems.
USP <645> CONDUCTIVITY REQUIREMENTS
Another important chapter in the regulatory environment is USP <645>, which covers conductivity.
USP <645> provides many details about how the system should be designed. The chapter describes the requirements for conductivity measurement, including how conductivity cell constants should be known and verified. It also describes how meter calibration should be performed using a traceable precision resistor, and how accurate the instrument should be in terms of conductivity and temperature.
The chapter also explains how system verification should be performed using an external calibrated conductivity measuring device, including the acceptable difference between the external device and the instrument.
These details in USP <645> have a real impact on the design and selection of an analyzer when users need to ensure compliance.
USP <643> TOC REQUIREMENTS
Similarly, USP <643> provides details on the requirements for total organic carbon analysis.
The chapter mentions the expected limit of detection of the system. The instrumentation should be able to reach 0.05 mg/L of carbon, which is approximately 50 ppb. In many cases, we are dealing with multiple units, including milligrams per liter and parts per billion, but here the requirement is approximately 50 ppb.
The chapter also describes how the system suitability test should be performed and what type of solutions should be used. In this case, the solutions are sucrose and 1,4-benzoquinone [confirm against audio/source slide]. The chapter sets the response efficiency requirement: response efficiency should be not less than 85% and not more than 115% of the theoretical response.
The chapter goes further by describing the objective of the instrument. The instrument should oxidize organic molecules so they produce carbon dioxide, which is then measured to determine the amount of total organic carbon.
The chapter also explains that the system must discriminate between inorganic carbon and the carbon dioxide generated from the oxidation of organic molecules. You do not want to mix those signals; they need to be measured separately.
There are two acceptable ways to discriminate between inorganic and organic carbon. One approach is to measure total inorganic carbon and subtract it from total carbon. The other approach is to remove, or purge, the inorganic carbon before oxidation and then oxidize the sample to assess the amount of organic carbon.
EUROPEAN PHARMACOPOEIA CHAPTER 2.2.44
The European Pharmacopoeia chapter 2.2.44 focuses on total organic carbon in water for pharmaceutical use. It is very similar to USP <643>.
You will find details about the system suitability test, and these requirements are well aligned with USP. Response efficiency should be not less than 85% and not more than 115% of the theoretical response.
The chapter is also aligned with USP on the objective of oxidizing organic molecules. However, it goes further by emphasizing that organic molecules must be completely oxidized. This is very important because if the molecules are not fully oxidized, the final result may be biased. You may miss some of the organic carbon.
The European Pharmacopoeia also defines the need to discriminate between organic carbon and inorganic carbon. It describes two accepted methods: either subtracting total inorganic carbon from total carbon, or removing inorganic carbon before oxidation and then oxidizing the remaining organic carbon.
Overall, the U.S. Pharmacopeia and European Pharmacopoeia are well aligned in terms of TOC requirements.
COMPARISON OF USP AND EUROPEAN PHARMACOPOEIA REQUIREMENTS
There are a few differences and many similarities between the U.S. Pharmacopeia and the European Pharmacopoeia.
For example, if you look at purified water and conductivity, USP asks for 1.3 uS/cm, while the European Pharmacopoeia asks for 5.1 uS/cm [confirm values against source slide]. This is probably one of the main differences.
For water for injection, USP and the European Pharmacopoeia are mostly aligned in terms of conductivity. For total organic carbon, they are also aligned. I kept the units used in the official text: 0.5 mg/L, which is equivalent to 500 ppb [confirm value against source slide].
For TOC measurement, there is full alignment between the two. The European Pharmacopoeia emphasizes that organic molecules must be completely oxidized. The system must also discriminate between organic and inorganic carbon, either by removing inorganic carbon before oxidation or by measuring inorganic carbon and subtracting it from total carbon.
The chapters are also aligned in terms of calibration and system suitability testing, including the use of sucrose and 1,4-benzoquinone [confirm].
Now that we have reviewed the regulatory environment, let's discuss the different technologies used to perform TOC analysis. We will review NDIR-based technologies and conductivity-based technologies.
NDIR-BASED TOC TECHNOLOGIES
I will start with NDIR-based technologies. NDIR stands for non-dispersive infrared. This type of detector is used in some instruments to measure the amount of carbon dioxide generated from organic carbon.
There are two main technologies. The first is based on a furnace and the use of platinum as a catalyst for oxidation. In this approach, the sample is introduced into the system. A gas is used to sparge the sample and remove inorganic carbon. Once the inorganic carbon has been removed, the sample is introduced into the furnace with the catalyst. The catalyst helps oxidize the organic molecules, generating CO2. The CO2 is then measured by NDIR. By measuring the CO2, the system generates a peak, and by integrating that peak, it determines the amount of organic carbon.
Another technology is based on UV and persulfate oxidation. In this case, the sample is introduced into the system, and a reagent is used to purge and remove inorganic carbon. Once inorganic carbon has been removed, UV oxidation occurs, and the organic carbon can be measured.
The way these systems work is slightly different. In the case of the furnace, there is no real-time control of inorganic carbon removal. There is no detection of what is happening during that step, so users must assume that enough time has been allowed to remove inorganic carbon.
In the case of UV oxidation, such as with the Beckman Coulter QbD1200+ TOC analyzer, endpoint detection is used. For both inorganic carbon and organic carbon, the system monitors the signal. The sample and reagent are added, and inorganic carbon is purged. Only when the system returns to baseline does the UV lamp turn on. At that point, oxidation of organic molecules begins, and the system starts integrating the organic carbon signal.
With endpoint detection, the system integrates until the peak returns to baseline, helping ensure that the organic molecules have been fully oxidized.
This principle helps ensure that the system can discriminate between inorganic and organic carbon and completely oxidize the molecules. Typically, this type of technology is well suited for laboratory use, but it is not ideally suited for online analysis because it involves reagents or catalysts and is more appropriate for discrete analysis. These systems may move from one vial to another, but they are not as well suited to being connected directly to a process.
CONDUCTIVITY-BASED TOC TECHNOLOGIES
Another way to perform online TOC analysis is to use conductivity-based technologies. Conductivity is a relatively simple measurement, which makes it easier to integrate this type of instrument directly into a process for pharmaceutical water monitoring.
The first type of conductivity-based technology is flow-through technology. In these instruments, the sample flows continuously through the system. There are two main types: simple flow-through conductivity technology and membrane transfer conductivity technology.
In simple flow-through technology, the sample flows through the system and passes through a conductivity cell, which measures conductivity before oxidation. This measurement corresponds to total inorganic carbon. The sample is then exposed to UV light to oxidize organic molecules. A second conductivity measurement is performed after oxidation, providing the amount of total carbon. By subtracting total inorganic carbon from total carbon, the system calculates total organic carbon.
Membrane transfer technology works slightly differently. The sample enters the system and is split into two paths. One path is not exposed to UV light, while the other path is exposed to a UV lamp to oxidize organic molecules. A membrane allows only carbon dioxide to reach the conductivity cell. Cell one measures the sample that was not exposed to UV light, representing total inorganic carbon. Cell two measures the sample after oxidation, representing total carbon. The system subtracts the measurement from cell one from the measurement from cell two to calculate total organic carbon.
The main advantage of this type of technology is high throughput. It can provide many data points and many measurements over time.
The main drawback is that there is generally no confirmation that the sample has been fully oxidized. In most cases, the system does not know whether the sample was fully oxidized when it reached the second conductivity cell, or whether organic matter remained unoxidized.
This means there is no real sensor confirming that oxidation occurred as required by USP <643> and European Pharmacopoeia chapter 2.2.44. For example, if the UV lamp ages and UV output decreases, the sample may require more time for complete oxidation. If the system does not adjust for this, it may underestimate total organic carbon.
The same issue can occur if the flow rate increases. The sample may pass through the system faster, leaving less time for oxidation before it reaches the next conductivity cell. This can create bias in the measurement.
Another consideration is that these systems rely on two different conductivity cells. If there is drift between the two cells, even a small drift can lead to negative or inaccurate readings. In that case, users may need to perform an auto-zero procedure. During this process, the system is offline, which means data points from the process may be missed.
STOP-FLOW DIRECT CONDUCTOMETRIC TECHNOLOGY
Another conductivity-based technology used for online TOC analysis is stop-flow direct conductometric measurement, which is the technology used in the PAT700 TOC analyzer.
This technology uses a single conductivity sensor, eliminating the risk of drift between two different conductivity cells. The sample flows through the filter and heat exchanger and is then captured in the conductivity cell.
Once the sample is captured, the system starts the measurement. It first measures the baseline, which reflects the total inorganic carbon value. After this measurement, the UV lamp turns on and begins oxidizing the organic molecules. The system monitors the signal and uses endpoint detection.
As with the QbD1200+ system, endpoint detection allows the system to monitor the signal and determine when the signal has stabilized. When the signal is stable, the system performs the final measurement. This measurement represents total carbon. By subtracting total inorganic carbon from total carbon, the system calculates total organic carbon.
Thanks to endpoint detection, the system supports compliance with USP and European Pharmacopoeia requirements. Changes in UV output, flow rate, or the nature of the organic compounds do not affect the final measurement in the same way they can affect flow-through systems. If more time is needed to fully oxidize organic matter, the system takes the time required to complete oxidation and support compliance with the relevant chapters.
PAT700 KEY FEATURES
Now let's move to the final part of the webinar, which focuses on the PAT700 and its use of stop-flow direct conductometric technology.
The PAT700 is designed to support compliance with both USP and European Pharmacopoeia requirements. I will review some key features of the PAT700 and explain how they support compliance.
First, the concentration range. The system can measure from 0.5 to 2,000 ppb as carbon [confirm against source slide]. If you remember, the required detection limit is approximately 50 ppb, so the system supports this requirement. In practice, many water for injection systems operate at much lower TOC values than 50 ppb, so the system is well suited for pharmaceutical water monitoring.
The system uses endpoint detection, as discussed earlier. This provides measurements that are independent of cell drift, flow rate, UV intensity variations, pH changes, and similar factors.
The system also includes a UV efficiency monitoring system. The instrument has two UV lamps and monitors lamp intensity. When lamp one is operating and its efficiency drops below the defined threshold, the system automatically switches to lamp two. This helps maximize uptime because the system does not have to go down immediately when a UV lamp needs to be replaced. Users can schedule replacement of lamp one while the system continues operating with lamp two.
The PAT700 also has an integrated heat exchanger, allowing it to handle water from 1 to 95 degrees C [confirm exact range against source slide], which typically covers pharmaceutical water applications.
The system includes leak detection with automatic alerts if the oxidation cell is contaminated or if another issue is detected [confirm wording against audio/source slide].
The PAT700 also includes a dedicated clean-in-place mode, which facilitates integration with CIP or SIP processes [confirm whether speaker said CIP, SIP, or both].
Another important feature is the onboard Automated Standards Introduction System, also called the Oasis module. This module provides automated SOPs for calibration, validation, system suitability testing, grab sample analysis, and excursion mode.
The module can also be equipped with RFID technology, which reduces the need for manual data entry. Lot number, expiration date, and certified values can be imported automatically through RFID technology.
HOW PAT700 SUPPORTS USP <643> AND EP 2.2.44
Let's now look at how the PAT700 supports compliance with USP <643> and European Pharmacopoeia chapter 2.2.44.
One of the first important points is discrimination between TIC and TOC, or inorganic carbon and organic carbon. One accepted approach is to subtract the inorganic carbon value from the total carbon value, and this is exactly what the PAT700 does.
When the sample enters the cell, the system starts by measuring sample conductivity. This provides the baseline and reflects the total inorganic carbon value. The UV lamp then turns on and begins oxidizing the sample.
The system monitors the conductivity signal. When stability is reached, it performs the final conductivity measurement. This final measurement represents total carbon, which includes the original inorganic carbon plus the carbon generated from oxidized organic molecules. By subtracting inorganic carbon from total carbon, the system calculates TOC.
In this way, the PAT700 supports compliance with USP <643> and European Pharmacopoeia requirements by discriminating between TIC and TOC.
The second important point is the complete oxidation of organic matter. This is where endpoint detection is important. The system waits until the signal stabilizes. Depending on the organic compounds in the sample, this may happen quickly or may take more time. In all cases, the system adjusts its analysis time to reach the endpoint where organic matter has been oxidized.
This helps ensure that the PAT700 supports compliance, even if there are changes in flow rate, UV intensity, or the type of organic compounds present in the sample.
WHY ENDPOINT DETECTION MATTERS
The oxidation rate can be affected by the sample and by the instrument. It may depend on the type of organic compound, the concentration of organic material, the condition of the oxidation cell, the UV lamp output, sample flow rate, temperature, and other environmental factors.
For example, methanol and sucrose oxidize differently, even at the same concentration. Methanol may reach stability quickly, potentially within about 60 seconds. Sucrose behaves differently. It may reach a higher conductivity state as intermediate species are formed, and then the signal may decrease as oxidation continues. If the measurement is taken too early, the system could overestimate total carbon and therefore overestimate TOC.
The bias can go in either direction depending on the oxidation profile. Without endpoint detection, the user must decide what oxidation time to use and whether that time is sufficient for all possible organic compounds that could contaminate the system.
With the PAT700, the user does not have to make that assumption. The system monitors the signal and readapts the analysis time to ensure complete oxidation.
Another example is UV lamp aging. With a new UV lamp, sucrose may reach stability in approximately 400 seconds [confirm exact value against source slide]. If the lamp has aged and only provides 70% of the original UV output, it will take longer to reach full oxidation. In that case, the system may take up to approximately 725 seconds [confirm exact value against source slide].
Less UV output means oxidation takes longer. Without endpoint detection, it is difficult to know how to adjust the system. With endpoint detection, the system monitors the signal and ensures the analysis continues until the endpoint is reached.
Endpoint detection therefore helps make compliance easier and supports PAT700 performance over time.
USP <645> CONDUCTIVITY SUPPORT
At the beginning of the presentation, we reviewed USP <645>, which includes requirements related to the conductivity cell constant, resistance calibration, precision resistors, and analyzer calibration and maintenance.
The PAT700 supports compliance with USP <645>. The system can verify the conductivity cell constant using a certified conductivity solution through the Oasis module. It can also perform resistance calibration using a precision signal resistor.
The PAT700 is also designed for low maintenance. The service and calibration interval is 12 months [confirm against source slide]. The only routine service items that need to be replaced are the internal water filter and the UV lamp [confirm exact list against source slide].
OASIS MODULE AND RFID-ENABLED WORKFLOWS
I mentioned earlier the onboard Automated Standards Introduction System, or Oasis module. I want to spend a little more time on this because it is an important PAT700 feature.
The Oasis module is a four-bottle module that facilitates activities around the system. It supports TOC calibration by allowing users to place four bottles in the module, including a blank and three standards at defined concentrations, to calibrate the unit.
It also supports conductivity calibration. When users want to check conductivity cell constants, they can place the conductivity standard in the module.
The module also facilitates validation, system suitability testing, cleaning, grab sample analysis, and excursion sampling. Users place the bottles in the module, run the protocol, and the system automatically manages the process.
The excursion mode is especially important because it supports root cause analysis and helps address EU GMP Annex 1 expectations for investigation.
For example, if the system is monitoring a water loop and something goes wrong, a TOC or conductivity alarm may be triggered. The PAT700 can automatically withdraw a sample and fill two RFID-tagged bottles.
The first bottle can be analyzed immediately. If the TOC or conductivity measurement returns within limits, the event may have been an isolated incident. If the result remains out of specification, the excursion is confirmed.
The second bottle, sampled at the same time, can then be brought to the lab for root cause analysis. This is an important feature because it reduces the delay between the alarm and sample collection. Without this automatic excursion mode, someone would need to go to the process, collect a sample manually, and document the event, which could introduce delays.
Each bottle filled during an excursion can be associated with information such as the instrument serial number, date, time, TOC, and conductivity. This helps capture the sample and support the investigation requirements described in Annex 1.
SUMMARY: WHY ONLINE TOC ANALYSIS MATTERS
To summarize, online TOC analyzers play an essential role in monitoring pharmaceutical water quality.
They provide an overall measurement of organic carbon, regardless of the source. This means they can detect a wide range of organic contaminants, including residues from APIs, cleaning agents, excipients, and other potential environmental contaminants.
TOC is also widely accepted across the regulatory environment, with specific chapters describing how it should be used. It is easy to use and implement without requiring highly specialized personnel. It is fast and efficient, providing results in a short period of time. It is also cost-effective from both a capital investment and running cost perspective.
TOC analyzers are versatile. They are suitable for continuous monitoring, but they can also be used for other applications, such as clean-in-place processes.
CONCLUSION
In conclusion, the PAT700 analyzer is designed to support compliance with U.S. Pharmacopeia and European Pharmacopoeia chapters.
It also supports root cause analysis as described in EU GMP Annex 1, including section 6.14 [confirm section number against source slide]. It supports 21 CFR Part 11 compliance by providing TOC, conductivity, temperature, and analysis data.
The instrument includes features that help maximize uptime, including dual UV lamps, the Oasis module, and low cost of ownership. As mentioned earlier, the system has a 12-month service interval and does not require reagents. The routine service items are the internal water filter and UV lamp.
Thank you for your attention. We will now look at the questions in the chat and try to answer as many as possible today. If we do not have time to answer all of them, we will respond later.
Q&A SECTION
QUESTION 1: IS DIRECT CONDUCTOMETRY ABLE TO MEASURE LOW LEVELS OF TOC?
Yes. Direct conductometry is well suited for measuring low levels of TOC. It may even be an ideal technique for rigorous QC because it uses a single conductivity cell. Since the same conductivity cell is used for the measurements, there is no risk of drift between two different conductivity probes.
This is important at very low TOC levels. When two conductivity probes are used, any drift between them can create negative values or inaccurate readings. This may require an auto-zero procedure. With a single conductivity cell, the system avoids this issue and can achieve very low levels of TOC measurement.
QUESTION 2: IS THE PAT700 COMPLIANT WITH 21 CFR PART 11?
Yes. The PAT700 is designed for pharmaceutical environments and supports 21 CFR Part 11 compliance.
It supports core principles such as multi-user access levels, Active Directory group access, audit trail functionality, and built-in SOPs for calibration and system suitability testing. These features help support compliance with 21 CFR Part 11 requirements.
QUESTION 3: HOW CAN YOU ENSURE THERE IS NO DRIFT IN MEASUREMENTS WHEN SWITCHING FROM ONE UV LAMP TO ANOTHER?
The answer is endpoint detection.
When one UV lamp drops below the defined threshold, the system switches to the second UV lamp. At that point, the UV output may be different from the previous lamp. However, endpoint detection adjusts the analysis time to ensure that all organic matter is fully oxidized.
This means that the analysis time may change when the system switches from lamp one to lamp two, but the system still monitors the oxidation process and waits until the endpoint is reached. This helps ensure complete oxidation of organic matter.
QUESTION 4: IS RFID REQUIRED TO USE THE OASIS MODULE?
No, RFID is not required for most Oasis module functions. Users can perform calibration, system suitability testing, validation, grab sample analysis, and other workflows without RFID.
However, RFID is required for excursion sampling. In excursion mode, the system automatically collects a sample and writes information such as TOC, conductivity, concentration, resistance, instrument information, and time/date details to the RFID-tagged bottle [confirm exact metadata list against source slide].
RFID availability may depend on local country certifications because RFID uses radio frequencies. Users should contact their local Beckman Coulter Life Sciences representative to confirm whether RFID is available in their country.
QUESTION 5: WHAT IS THE MEASUREMENT TIME FOR A SAMPLE?
The answer depends on the sample.
Measurement time depends on the type and concentration of organic compounds, UV output, and other conditions. For low levels of TOC, the measurement time is typically around 4 to 5 minutes. In some cases, it can take up to 15 minutes.
The important point is that this time is used to maintain compliance with U.S. and European Pharmacopoeia requirements by allowing the system to reach endpoint detection and confirm complete oxidation.
CLOSING
I see there are many additional questions in the chat. I apologize that we may not be able to answer all of them live today, but thank you everyone for your attention. I was happy to present this topic, and if you have any additional questions, please feel free to reach out to your Beckman Coulter Life Sciences representative. Thank you.
Welcome to this webinar on online Total Organic Carbon, or TOC, analyzers, pharmacopeial requirements, and EU GMP Annex 1 requirements.
Before starting, I want to briefly show our intellectual property disclaimer, which I will let you read. I also want to mention that Beckman Coulter Life Sciences has been part of Danaher Corporation since 2011. Now, let's get started.
Today, I will first present the agenda. The first part of the webinar will focus on the regulatory environment, including an overview of the different chapters that apply to TOC analysis and pharmaceutical water. We will look in more detail at EU GMP Annex 1 requirements and European Pharmacopoeia requirements.
The second part of the webinar will focus on TOC analyzer technologies available on the market, including their advantages and drawbacks.
The final part will focus on the PAT700, the Beckman Coulter online TOC analyzer, and how it supports compliance with these requirements.
REGULATORY ENVIRONMENT
The regulatory environment for TOC analyzers comes from several different bodies. It includes the U.S. Pharmacopeia, the European Medicines Agency, or EMA, EU GMP, and the European Pharmacopoeia.
There are general chapters, such as USP <1231>, which provides guidance on water for pharmaceutical purposes. This type of general chapter provides information about the collection, validation, and testing of water used in pharmaceutical manufacturing. It covers aspects such as microbial water quality attributes and other important quality considerations.
There are also other general chapters, such as USP <643>, USP <645>, and European Pharmacopoeia chapter 2.2.44. These chapters provide more detail about total organic carbon and conductivity for water used in pharmaceutical production. They describe requirements for measuring TOC and conductivity in this type of water.
One difference between the U.S. Pharmacopeia and the European Pharmacopoeia is that USP <643> and USP <645> define both measurement requirements and water quality standards. In the European Pharmacopoeia, chapter 2.2.44 focuses on method requirements, while quality standards are defined in separate monographs, including those for purified water and water for injection.
EU GMP ANNEX 1 REQUIREMENTS
Let's now discuss EU GMP Annex 1 and the content of the revised text. The revised version was released in 2022, replacing the previous version from 2008. There are changes that directly affect how manufacturers monitor their water systems, including water for injection systems.
For example, in section 6.15, Annex 1 states that water for injection systems should include continuous monitoring for TOC and conductivity, making this type of monitoring mandatory.
If we look at the section on excursions, we also see that all local excursions should be documented and reviewed. The text also requires an investigation in the event of an excursion.
The way alert limits and action limits are defined is also pushing users toward more online analysis. Online monitoring allows users to monitor TOC and conductivity more closely and identify alert levels that provide early warning of drift. These alert levels can trigger follow-up scrutiny to address potential problems. Action limits represent a more serious deviation from normal operating conditions and should trigger immediate investigation and corrective actions.
Overall, the revised EU GMP Annex 1 places greater emphasis on the use of TOC monitoring for water for injection systems.
USP <645> CONDUCTIVITY REQUIREMENTS
Another important chapter in the regulatory environment is USP <645>, which covers conductivity.
USP <645> provides many details about how the system should be designed. The chapter describes the requirements for conductivity measurement, including how conductivity cell constants should be known and verified. It also describes how meter calibration should be performed using a traceable precision resistor, and how accurate the instrument should be in terms of conductivity and temperature.
The chapter also explains how system verification should be performed using an external calibrated conductivity measuring device, including the acceptable difference between the external device and the instrument.
These details in USP <645> have a real impact on the design and selection of an analyzer when users need to ensure compliance.
USP <643> TOC REQUIREMENTS
Similarly, USP <643> provides details on the requirements for total organic carbon analysis.
The chapter mentions the expected limit of detection of the system. The instrumentation should be able to reach 0.05 mg/L of carbon, which is approximately 50 ppb. In many cases, we are dealing with multiple units, including milligrams per liter and parts per billion, but here the requirement is approximately 50 ppb.
The chapter also describes how the system suitability test should be performed and what type of solutions should be used. In this case, the solutions are sucrose and 1,4-benzoquinone [confirm against audio/source slide]. The chapter sets the response efficiency requirement: response efficiency should be not less than 85% and not more than 115% of the theoretical response.
The chapter goes further by describing the objective of the instrument. The instrument should oxidize organic molecules so they produce carbon dioxide, which is then measured to determine the amount of total organic carbon.
The chapter also explains that the system must discriminate between inorganic carbon and the carbon dioxide generated from the oxidation of organic molecules. You do not want to mix those signals; they need to be measured separately.
There are two acceptable ways to discriminate between inorganic and organic carbon. One approach is to measure total inorganic carbon and subtract it from total carbon. The other approach is to remove, or purge, the inorganic carbon before oxidation and then oxidize the sample to assess the amount of organic carbon.
EUROPEAN PHARMACOPOEIA CHAPTER 2.2.44
The European Pharmacopoeia chapter 2.2.44 focuses on total organic carbon in water for pharmaceutical use. It is very similar to USP <643>.
You will find details about the system suitability test, and these requirements are well aligned with USP. Response efficiency should be not less than 85% and not more than 115% of the theoretical response.
The chapter is also aligned with USP on the objective of oxidizing organic molecules. However, it goes further by emphasizing that organic molecules must be completely oxidized. This is very important because if the molecules are not fully oxidized, the final result may be biased. You may miss some of the organic carbon.
The European Pharmacopoeia also defines the need to discriminate between organic carbon and inorganic carbon. It describes two accepted methods: either subtracting total inorganic carbon from total carbon, or removing inorganic carbon before oxidation and then oxidizing the remaining organic carbon.
Overall, the U.S. Pharmacopeia and European Pharmacopoeia are well aligned in terms of TOC requirements.
COMPARISON OF USP AND EUROPEAN PHARMACOPOEIA REQUIREMENTS
There are a few differences and many similarities between the U.S. Pharmacopeia and the European Pharmacopoeia.
For example, if you look at purified water and conductivity, USP asks for 1.3 uS/cm, while the European Pharmacopoeia asks for 5.1 uS/cm [confirm values against source slide]. This is probably one of the main differences.
For water for injection, USP and the European Pharmacopoeia are mostly aligned in terms of conductivity. For total organic carbon, they are also aligned. I kept the units used in the official text: 0.5 mg/L, which is equivalent to 500 ppb [confirm value against source slide].
For TOC measurement, there is full alignment between the two. The European Pharmacopoeia emphasizes that organic molecules must be completely oxidized. The system must also discriminate between organic and inorganic carbon, either by removing inorganic carbon before oxidation or by measuring inorganic carbon and subtracting it from total carbon.
The chapters are also aligned in terms of calibration and system suitability testing, including the use of sucrose and 1,4-benzoquinone [confirm].
Now that we have reviewed the regulatory environment, let's discuss the different technologies used to perform TOC analysis. We will review NDIR-based technologies and conductivity-based technologies.
NDIR-BASED TOC TECHNOLOGIES
I will start with NDIR-based technologies. NDIR stands for non-dispersive infrared. This type of detector is used in some instruments to measure the amount of carbon dioxide generated from organic carbon.
There are two main technologies. The first is based on a furnace and the use of platinum as a catalyst for oxidation. In this approach, the sample is introduced into the system. A gas is used to sparge the sample and remove inorganic carbon. Once the inorganic carbon has been removed, the sample is introduced into the furnace with the catalyst. The catalyst helps oxidize the organic molecules, generating CO2. The CO2 is then measured by NDIR. By measuring the CO2, the system generates a peak, and by integrating that peak, it determines the amount of organic carbon.
Another technology is based on UV and persulfate oxidation. In this case, the sample is introduced into the system, and a reagent is used to purge and remove inorganic carbon. Once inorganic carbon has been removed, UV oxidation occurs, and the organic carbon can be measured.
The way these systems work is slightly different. In the case of the furnace, there is no real-time control of inorganic carbon removal. There is no detection of what is happening during that step, so users must assume that enough time has been allowed to remove inorganic carbon.
In the case of UV oxidation, such as with the Beckman Coulter QbD1200+ TOC analyzer, endpoint detection is used. For both inorganic carbon and organic carbon, the system monitors the signal. The sample and reagent are added, and inorganic carbon is purged. Only when the system returns to baseline does the UV lamp turn on. At that point, oxidation of organic molecules begins, and the system starts integrating the organic carbon signal.
With endpoint detection, the system integrates until the peak returns to baseline, helping ensure that the organic molecules have been fully oxidized.
This principle helps ensure that the system can discriminate between inorganic and organic carbon and completely oxidize the molecules. Typically, this type of technology is well suited for laboratory use, but it is not ideally suited for online analysis because it involves reagents or catalysts and is more appropriate for discrete analysis. These systems may move from one vial to another, but they are not as well suited to being connected directly to a process.
CONDUCTIVITY-BASED TOC TECHNOLOGIES
Another way to perform online TOC analysis is to use conductivity-based technologies. Conductivity is a relatively simple measurement, which makes it easier to integrate this type of instrument directly into a process for pharmaceutical water monitoring.
The first type of conductivity-based technology is flow-through technology. In these instruments, the sample flows continuously through the system. There are two main types: simple flow-through conductivity technology and membrane transfer conductivity technology.
In simple flow-through technology, the sample flows through the system and passes through a conductivity cell, which measures conductivity before oxidation. This measurement corresponds to total inorganic carbon. The sample is then exposed to UV light to oxidize organic molecules. A second conductivity measurement is performed after oxidation, providing the amount of total carbon. By subtracting total inorganic carbon from total carbon, the system calculates total organic carbon.
Membrane transfer technology works slightly differently. The sample enters the system and is split into two paths. One path is not exposed to UV light, while the other path is exposed to a UV lamp to oxidize organic molecules. A membrane allows only carbon dioxide to reach the conductivity cell. Cell one measures the sample that was not exposed to UV light, representing total inorganic carbon. Cell two measures the sample after oxidation, representing total carbon. The system subtracts the measurement from cell one from the measurement from cell two to calculate total organic carbon.
The main advantage of this type of technology is high throughput. It can provide many data points and many measurements over time.
The main drawback is that there is generally no confirmation that the sample has been fully oxidized. In most cases, the system does not know whether the sample was fully oxidized when it reached the second conductivity cell, or whether organic matter remained unoxidized.
This means there is no real sensor confirming that oxidation occurred as required by USP <643> and European Pharmacopoeia chapter 2.2.44. For example, if the UV lamp ages and UV output decreases, the sample may require more time for complete oxidation. If the system does not adjust for this, it may underestimate total organic carbon.
The same issue can occur if the flow rate increases. The sample may pass through the system faster, leaving less time for oxidation before it reaches the next conductivity cell. This can create bias in the measurement.
Another consideration is that these systems rely on two different conductivity cells. If there is drift between the two cells, even a small drift can lead to negative or inaccurate readings. In that case, users may need to perform an auto-zero procedure. During this process, the system is offline, which means data points from the process may be missed.
STOP-FLOW DIRECT CONDUCTOMETRIC TECHNOLOGY
Another conductivity-based technology used for online TOC analysis is stop-flow direct conductometric measurement, which is the technology used in the PAT700 TOC analyzer.
This technology uses a single conductivity sensor, eliminating the risk of drift between two different conductivity cells. The sample flows through the filter and heat exchanger and is then captured in the conductivity cell.
Once the sample is captured, the system starts the measurement. It first measures the baseline, which reflects the total inorganic carbon value. After this measurement, the UV lamp turns on and begins oxidizing the organic molecules. The system monitors the signal and uses endpoint detection.
As with the QbD1200+ system, endpoint detection allows the system to monitor the signal and determine when the signal has stabilized. When the signal is stable, the system performs the final measurement. This measurement represents total carbon. By subtracting total inorganic carbon from total carbon, the system calculates total organic carbon.
Thanks to endpoint detection, the system supports compliance with USP and European Pharmacopoeia requirements. Changes in UV output, flow rate, or the nature of the organic compounds do not affect the final measurement in the same way they can affect flow-through systems. If more time is needed to fully oxidize organic matter, the system takes the time required to complete oxidation and support compliance with the relevant chapters.
PAT700 KEY FEATURES
Now let's move to the final part of the webinar, which focuses on the PAT700 and its use of stop-flow direct conductometric technology.
The PAT700 is designed to support compliance with both USP and European Pharmacopoeia requirements. I will review some key features of the PAT700 and explain how they support compliance.
First, the concentration range. The system can measure from 0.5 to 2,000 ppb as carbon [confirm against source slide]. If you remember, the required detection limit is approximately 50 ppb, so the system supports this requirement. In practice, many water for injection systems operate at much lower TOC values than 50 ppb, so the system is well suited for pharmaceutical water monitoring.
The system uses endpoint detection, as discussed earlier. This provides measurements that are independent of cell drift, flow rate, UV intensity variations, pH changes, and similar factors.
The system also includes a UV efficiency monitoring system. The instrument has two UV lamps and monitors lamp intensity. When lamp one is operating and its efficiency drops below the defined threshold, the system automatically switches to lamp two. This helps maximize uptime because the system does not have to go down immediately when a UV lamp needs to be replaced. Users can schedule replacement of lamp one while the system continues operating with lamp two.
The PAT700 also has an integrated heat exchanger, allowing it to handle water from 1 to 95 degrees C [confirm exact range against source slide], which typically covers pharmaceutical water applications.
The system includes leak detection with automatic alerts if the oxidation cell is contaminated or if another issue is detected [confirm wording against audio/source slide].
The PAT700 also includes a dedicated clean-in-place mode, which facilitates integration with CIP or SIP processes [confirm whether speaker said CIP, SIP, or both].
Another important feature is the onboard Automated Standards Introduction System, also called the Oasis module. This module provides automated SOPs for calibration, validation, system suitability testing, grab sample analysis, and excursion mode.
The module can also be equipped with RFID technology, which reduces the need for manual data entry. Lot number, expiration date, and certified values can be imported automatically through RFID technology.
HOW PAT700 SUPPORTS USP <643> AND EP 2.2.44
Let's now look at how the PAT700 supports compliance with USP <643> and European Pharmacopoeia chapter 2.2.44.
One of the first important points is discrimination between TIC and TOC, or inorganic carbon and organic carbon. One accepted approach is to subtract the inorganic carbon value from the total carbon value, and this is exactly what the PAT700 does.
When the sample enters the cell, the system starts by measuring sample conductivity. This provides the baseline and reflects the total inorganic carbon value. The UV lamp then turns on and begins oxidizing the sample.
The system monitors the conductivity signal. When stability is reached, it performs the final conductivity measurement. This final measurement represents total carbon, which includes the original inorganic carbon plus the carbon generated from oxidized organic molecules. By subtracting inorganic carbon from total carbon, the system calculates TOC.
In this way, the PAT700 supports compliance with USP <643> and European Pharmacopoeia requirements by discriminating between TIC and TOC.
The second important point is the complete oxidation of organic matter. This is where endpoint detection is important. The system waits until the signal stabilizes. Depending on the organic compounds in the sample, this may happen quickly or may take more time. In all cases, the system adjusts its analysis time to reach the endpoint where organic matter has been oxidized.
This helps ensure that the PAT700 supports compliance, even if there are changes in flow rate, UV intensity, or the type of organic compounds present in the sample.
WHY ENDPOINT DETECTION MATTERS
The oxidation rate can be affected by the sample and by the instrument. It may depend on the type of organic compound, the concentration of organic material, the condition of the oxidation cell, the UV lamp output, sample flow rate, temperature, and other environmental factors.
For example, methanol and sucrose oxidize differently, even at the same concentration. Methanol may reach stability quickly, potentially within about 60 seconds. Sucrose behaves differently. It may reach a higher conductivity state as intermediate species are formed, and then the signal may decrease as oxidation continues. If the measurement is taken too early, the system could overestimate total carbon and therefore overestimate TOC.
The bias can go in either direction depending on the oxidation profile. Without endpoint detection, the user must decide what oxidation time to use and whether that time is sufficient for all possible organic compounds that could contaminate the system.
With the PAT700, the user does not have to make that assumption. The system monitors the signal and readapts the analysis time to ensure complete oxidation.
Another example is UV lamp aging. With a new UV lamp, sucrose may reach stability in approximately 400 seconds [confirm exact value against source slide]. If the lamp has aged and only provides 70% of the original UV output, it will take longer to reach full oxidation. In that case, the system may take up to approximately 725 seconds [confirm exact value against source slide].
Less UV output means oxidation takes longer. Without endpoint detection, it is difficult to know how to adjust the system. With endpoint detection, the system monitors the signal and ensures the analysis continues until the endpoint is reached.
Endpoint detection therefore helps make compliance easier and supports PAT700 performance over time.
USP <645> CONDUCTIVITY SUPPORT
At the beginning of the presentation, we reviewed USP <645>, which includes requirements related to the conductivity cell constant, resistance calibration, precision resistors, and analyzer calibration and maintenance.
The PAT700 supports compliance with USP <645>. The system can verify the conductivity cell constant using a certified conductivity solution through the Oasis module. It can also perform resistance calibration using a precision signal resistor.
The PAT700 is also designed for low maintenance. The service and calibration interval is 12 months [confirm against source slide]. The only routine service items that need to be replaced are the internal water filter and the UV lamp [confirm exact list against source slide].
OASIS MODULE AND RFID-ENABLED WORKFLOWS
I mentioned earlier the onboard Automated Standards Introduction System, or Oasis module. I want to spend a little more time on this because it is an important PAT700 feature.
The Oasis module is a four-bottle module that facilitates activities around the system. It supports TOC calibration by allowing users to place four bottles in the module, including a blank and three standards at defined concentrations, to calibrate the unit.
It also supports conductivity calibration. When users want to check conductivity cell constants, they can place the conductivity standard in the module.
The module also facilitates validation, system suitability testing, cleaning, grab sample analysis, and excursion sampling. Users place the bottles in the module, run the protocol, and the system automatically manages the process.
The excursion mode is especially important because it supports root cause analysis and helps address EU GMP Annex 1 expectations for investigation.
For example, if the system is monitoring a water loop and something goes wrong, a TOC or conductivity alarm may be triggered. The PAT700 can automatically withdraw a sample and fill two RFID-tagged bottles.
The first bottle can be analyzed immediately. If the TOC or conductivity measurement returns within limits, the event may have been an isolated incident. If the result remains out of specification, the excursion is confirmed.
The second bottle, sampled at the same time, can then be brought to the lab for root cause analysis. This is an important feature because it reduces the delay between the alarm and sample collection. Without this automatic excursion mode, someone would need to go to the process, collect a sample manually, and document the event, which could introduce delays.
Each bottle filled during an excursion can be associated with information such as the instrument serial number, date, time, TOC, and conductivity. This helps capture the sample and support the investigation requirements described in Annex 1.
SUMMARY: WHY ONLINE TOC ANALYSIS MATTERS
To summarize, online TOC analyzers play an essential role in monitoring pharmaceutical water quality.
They provide an overall measurement of organic carbon, regardless of the source. This means they can detect a wide range of organic contaminants, including residues from APIs, cleaning agents, excipients, and other potential environmental contaminants.
TOC is also widely accepted across the regulatory environment, with specific chapters describing how it should be used. It is easy to use and implement without requiring highly specialized personnel. It is fast and efficient, providing results in a short period of time. It is also cost-effective from both a capital investment and running cost perspective.
TOC analyzers are versatile. They are suitable for continuous monitoring, but they can also be used for other applications, such as clean-in-place processes.
CONCLUSION
In conclusion, the PAT700 analyzer is designed to support compliance with U.S. Pharmacopeia and European Pharmacopoeia chapters.
It also supports root cause analysis as described in EU GMP Annex 1, including section 6.14 [confirm section number against source slide]. It supports 21 CFR Part 11 compliance by providing TOC, conductivity, temperature, and analysis data.
The instrument includes features that help maximize uptime, including dual UV lamps, the Oasis module, and low cost of ownership. As mentioned earlier, the system has a 12-month service interval and does not require reagents. The routine service items are the internal water filter and UV lamp.
Thank you for your attention. We will now look at the questions in the chat and try to answer as many as possible today. If we do not have time to answer all of them, we will respond later.
Q&A SECTION
QUESTION 1: IS DIRECT CONDUCTOMETRY ABLE TO MEASURE LOW LEVELS OF TOC?
Yes. Direct conductometry is well suited for measuring low levels of TOC. It may even be an ideal technique for rigorous QC because it uses a single conductivity cell. Since the same conductivity cell is used for the measurements, there is no risk of drift between two different conductivity probes.
This is important at very low TOC levels. When two conductivity probes are used, any drift between them can create negative values or inaccurate readings. This may require an auto-zero procedure. With a single conductivity cell, the system avoids this issue and can achieve very low levels of TOC measurement.
QUESTION 2: IS THE PAT700 COMPLIANT WITH 21 CFR PART 11?
Yes. The PAT700 is designed for pharmaceutical environments and supports 21 CFR Part 11 compliance.
It supports core principles such as multi-user access levels, Active Directory group access, audit trail functionality, and built-in SOPs for calibration and system suitability testing. These features help support compliance with 21 CFR Part 11 requirements.
QUESTION 3: HOW CAN YOU ENSURE THERE IS NO DRIFT IN MEASUREMENTS WHEN SWITCHING FROM ONE UV LAMP TO ANOTHER?
The answer is endpoint detection.
When one UV lamp drops below the defined threshold, the system switches to the second UV lamp. At that point, the UV output may be different from the previous lamp. However, endpoint detection adjusts the analysis time to ensure that all organic matter is fully oxidized.
This means that the analysis time may change when the system switches from lamp one to lamp two, but the system still monitors the oxidation process and waits until the endpoint is reached. This helps ensure complete oxidation of organic matter.
QUESTION 4: IS RFID REQUIRED TO USE THE OASIS MODULE?
No, RFID is not required for most Oasis module functions. Users can perform calibration, system suitability testing, validation, grab sample analysis, and other workflows without RFID.
However, RFID is required for excursion sampling. In excursion mode, the system automatically collects a sample and writes information such as TOC, conductivity, concentration, resistance, instrument information, and time/date details to the RFID-tagged bottle [confirm exact metadata list against source slide].
RFID availability may depend on local country certifications because RFID uses radio frequencies. Users should contact their local Beckman Coulter Life Sciences representative to confirm whether RFID is available in their country.
QUESTION 5: WHAT IS THE MEASUREMENT TIME FOR A SAMPLE?
The answer depends on the sample.
Measurement time depends on the type and concentration of organic compounds, UV output, and other conditions. For low levels of TOC, the measurement time is typically around 4 to 5 minutes. In some cases, it can take up to 15 minutes.
The important point is that this time is used to maintain compliance with U.S. and European Pharmacopoeia requirements by allowing the system to reach endpoint detection and confirm complete oxidation.
CLOSING
I see there are many additional questions in the chat. I apologize that we may not be able to answer all of them live today, but thank you everyone for your attention. I was happy to present this topic, and if you have any additional questions, please feel free to reach out to your Beckman Coulter Life Sciences representative. Thank you.
