Pharmaceutical manufacturers need to focus on quality and cost effectiveness. The quality of the sample is usually assessed in the laboratory by the pharmaceutical company. The FDA has encouraged the pharmaceutical industry to use the online tools described in the PAT Action Plan to better understand and control the manufacturing process.
This white paper will focus on new technologies for assisting in the measurement of pH and dissolved oxygen in bioreactors and in product purification and downstream processing. The measurement of pH and dissolved oxygen is still a traditional tool. Intelligent Sensor Management (ISM) is a breakthrough improvement to these measurement parameters that provides diagnostic tools that help optimize process life, performance and reliability of process analysis equipment. Predicting before the problem occurs is much better than responding quickly when the sensor fails. Intelligent sensor management means improved process safety and productivity, and reduced downtime.
For a variety of reasons, the pharmaceutical industry is reluctant to adopt new technologies in its own manufacturing process. One reason is that they believe current regulations are not good for implementing new systems. This reluctance will eventually change, because the industry benefits from the use of new technologies to shorten the pharmaceutical cycle, speed time to market, and improve the quality of medicines.
After recognizing the need to transform the perceptions of the pharmaceutical industry, the FDA launched a new action plan called "21st Century Good Manufacturing Practices: Risk-Based Initiatives" in 2002. The program has led the FDA to actively call for the use of Process Analytical Technology (PAT) tools with the goal of enabling pharmaceutical companies to better “understand and control the manufacturing process†(http://). These PAT technologies include continuous improvement and knowledge management tools as well as data acquisition and analysis tools.
When discussing the PAT in the early days of the pharmaceutical industry, it was often considered as a step toward achieving the PAT compliance goal by implementing more analytical measurements in the process. However, PAT is neither used to improve the subtleties of the process nor to better control bad processes. The goal is to move toward a larger vision of designing, monitoring and controlling the entire manufacturing process in a holistic manner to ensure efficient and reliable conversion of raw materials into high quality products. This does not mean that the FDA expects pharmaceutical companies to invest in expensive analytical equipment.
“PAT emphasizes understanding and control processes, not trying to find exotic technologies for this.†(Ajaz Hussain, former FDA Deputy Director – Pharmaceutical Technology (October 2004)).
As will be explained in this white paper, process analysis tools for measuring pH, dissolved oxygen, etc. play an important role in helping pharmaceutical manufacturers achieve PAT goals.
Intelligent sensor management As a PAT tool, in the pharmaceutical process, the downstream processing stage usually requires more expenses. In view of this, the use of PAT tools and technologies is very beneficial to shorten the production cycle and reduce costs at this stage.
To help achieve this goal, analytical measurement points must provide accurate and real-time information to ensure that target process parameter drift is detected as early as possible. In addition, the sensor should be easy to maintain, have a long service life and be highly reliable, as accidental shutdowns due to sensor failure can cause significant economic losses.
A new analog-to-digital converter and built-in memory is a revolutionary innovation in digital pH and dissolved oxygen measurements. Sensors for inductive, non-contact, plug-and-play connectors are available on the market to avoid problems such as moisture and corrosion. In addition, low impedance digital signals are not affected by moisture. The METTLER TOLEDO Digital ISM sensor has state-of-the-art diagnostics and is the ideal solution for time-consuming calibration and maintenance operations.
ISM-enabled sensors store their unique data along with calibration data and data about the current process in a built-in chip and automatically transfer it to the connected transmitter.
ISM technology provides professional information tailored to each measurement point. The ISM system uses the “Advanced Diagnostics†measurement function to save all data related to the sensor and process and display it in detail on the transmitter's graphical interface. This ensures that the measurement points are continually optimized because all important situations can be predicted and corrective actions taken early before production interruptions. For example, monitoring pH is critical for pH measurement. The ISM provides online glass impedance and reference monitoring. These data are graphically summarized on the sensor grid map and displayed on the transmitter (Figure 1). In the event that either or both of the impedance readings deviate too far from the center point of the network diagram, an impending failure is indicated, which can be replaced before the sensor fails.
Figure 1: Visual Reference System Monitoring by Sensor Performance Grid Diagram to Determine Sensor Dissipation A diagnostic parameter called “sensor wear level†can indicate the degree of change in the condition of a sensor used in a process (Figure 2). Taking the above impedance example as an example, it is possible to replace a sensor with a high degree of loss before it fails during operation, which can reduce the number of accidental interruptions. The maximum zui loss allowed for each measurement point can be individually adjusted to adjust to the level of confidence required for the process. In this way, maintenance strategies can be changed from passive, expensive and unpredictable workflows to fully proactive optimization processes. This is an example of continuous improvement and an aspect of the PAT action plan.
Figure 2: Part of the function of actively maintaining the sensor wear level parameter through the sensor wear level monitor is to monitor the CIP and SIP cycle frequencies. These are critical for proper functioning of pH and dissolved oxygen sensors during batch processes; however, they can adversely affect the slope of the sensor, resulting in improper measurement and premature sensor failure. To solve this problem, plant operators typically manually record the historical data of the sensor and develop a maintenance plan accordingly. The ISM sensor has a built-in CIP and SIP counter that detects when the sensor is used for thermal cycling. This data is stored in the embedded chip and then automatically uploaded to the transmitter. An alarm will be issued when the set number of cycles of zui is exceeded. This avoids the use of sensors that are likely to fail during the process.
The iSense Asset Kit is digitally signalable from the ISM sensor, so it can be connected to a PC or laptop via the USB port. This allows the sensor to communicate with the METTLER TOLEDO iSenseAssetSuite software, which provides different analysis, calibration and documentation tools. The key performance meter allows you to evaluate the condition of the ISM sensor at a glance without the need for a transmitter. One of the more useful features of the iSense software is the ability to calibrate the sensor from a PC/laptop. Since accurate pre-calibration in the laboratory results in superior performance in field applications, this is a huge advantage for large bioreactors, further enabling PAT targets.
Optical Oxygen Sensor During the fermentation process, the gas supply and agitation speed are adjusted according to the measured dissolved oxygen concentration value, thereby providing a good growth environment for the microorganism. Mammalian cell culture is increasingly used in the pharmaceutical industry, but mammalian cell culture is more sensitive to environmental changes than bacterial culture, and its growth rate is rather slow. In the full five-week batch production, the optical oxygen sensor fully proves its strength, that is, only a slight drift occurs during a long period of time. Stable measurements ensure batch consistency, which is another goal of PAT while maintaining a good growth environment. METTLER TOLEDO's new optical oxygen sensors are used in small, high pressure heated bioreactors and large production scale reactors.
iSenseISMAssetSuite
The built-in ISM technology in the sensor has a “plug and measure†function that ensures fast start-up and provides advanced diagnostics as described above. The ISM can help determine if the sensor is safe to use again in the next batch, or if maintenance is required (such as membrane replacement). In addition, optical sensors have good availability because they do not require polarization operations compared to polarographic sensors.
The core of the optical sensor is an oxygen sensitive layer containing immobilized label molecules. They absorb light from the light-emitting diodes and are capable of releasing energy at different wavelengths of light (fluorescence). Fluorescence depends on the amount of oxygen in the environment of the labeled molecule. This effect can be used to determine the oxygen concentration in the sample medium.
The measurement point verification ISM verification kit ensures that the measurement points can be verified without the use of sensors in accordance with GMP regulations. A system of five devices can simulate two fixed values ​​at different temperatures and different error conditions. It also verifies important ISM parameters such as SIP/CIP counters and dynamic life indicator.
Turbidity Sensor The online turbidity sensor provides real-time readings of the amount of light scattered by the cell suspension. This is because the turbidity of the cell suspension is directly related to the number of cells and is highly correlated with the optical density measurement. Knowing turbidity means that microbial activity in continuous culture can be controlled by adjusting the addition of nutrients and the rate of removal of the bioreactor medium. If this activity is copied into this process, the online turbidity measurement is also consistent with the PAT target.
Conclusion The recommendations in the PAT Action Plan are only recommendations, not rules. However, this does not mean that the pharmaceutical industry should continue to treat the new procedures reluctantly before the relevant regulations are introduced.
As shown above, the use of METTLER TOLEDO process analysis sensors with ISM technology ensures a better understanding of bioprocess and online monitoring, which is essential for feedback control and ensuring consistent quality. The ability to be compatible with PAT is inextricably linked to understanding and using the data provided by METTLER TOLEDO technology. In addition, ISM sensors help improve batch quality, reduce unplanned downtime, and reduce maintenance burden, all in line with the PAT Action Plan.
This white paper will focus on new technologies for assisting in the measurement of pH and dissolved oxygen in bioreactors and in product purification and downstream processing. The measurement of pH and dissolved oxygen is still a traditional tool. Intelligent Sensor Management (ISM) is a breakthrough improvement to these measurement parameters that provides diagnostic tools that help optimize process life, performance and reliability of process analysis equipment. Predicting before the problem occurs is much better than responding quickly when the sensor fails. Intelligent sensor management means improved process safety and productivity, and reduced downtime.
For a variety of reasons, the pharmaceutical industry is reluctant to adopt new technologies in its own manufacturing process. One reason is that they believe current regulations are not good for implementing new systems. This reluctance will eventually change, because the industry benefits from the use of new technologies to shorten the pharmaceutical cycle, speed time to market, and improve the quality of medicines.
After recognizing the need to transform the perceptions of the pharmaceutical industry, the FDA launched a new action plan called "21st Century Good Manufacturing Practices: Risk-Based Initiatives" in 2002. The program has led the FDA to actively call for the use of Process Analytical Technology (PAT) tools with the goal of enabling pharmaceutical companies to better “understand and control the manufacturing process†(http://). These PAT technologies include continuous improvement and knowledge management tools as well as data acquisition and analysis tools.
When discussing the PAT in the early days of the pharmaceutical industry, it was often considered as a step toward achieving the PAT compliance goal by implementing more analytical measurements in the process. However, PAT is neither used to improve the subtleties of the process nor to better control bad processes. The goal is to move toward a larger vision of designing, monitoring and controlling the entire manufacturing process in a holistic manner to ensure efficient and reliable conversion of raw materials into high quality products. This does not mean that the FDA expects pharmaceutical companies to invest in expensive analytical equipment.
“PAT emphasizes understanding and control processes, not trying to find exotic technologies for this.†(Ajaz Hussain, former FDA Deputy Director – Pharmaceutical Technology (October 2004)).
As will be explained in this white paper, process analysis tools for measuring pH, dissolved oxygen, etc. play an important role in helping pharmaceutical manufacturers achieve PAT goals.
Intelligent sensor management As a PAT tool, in the pharmaceutical process, the downstream processing stage usually requires more expenses. In view of this, the use of PAT tools and technologies is very beneficial to shorten the production cycle and reduce costs at this stage.
To help achieve this goal, analytical measurement points must provide accurate and real-time information to ensure that target process parameter drift is detected as early as possible. In addition, the sensor should be easy to maintain, have a long service life and be highly reliable, as accidental shutdowns due to sensor failure can cause significant economic losses.
A new analog-to-digital converter and built-in memory is a revolutionary innovation in digital pH and dissolved oxygen measurements. Sensors for inductive, non-contact, plug-and-play connectors are available on the market to avoid problems such as moisture and corrosion. In addition, low impedance digital signals are not affected by moisture. The METTLER TOLEDO Digital ISM sensor has state-of-the-art diagnostics and is the ideal solution for time-consuming calibration and maintenance operations.
ISM-enabled sensors store their unique data along with calibration data and data about the current process in a built-in chip and automatically transfer it to the connected transmitter.
ISM technology provides professional information tailored to each measurement point. The ISM system uses the “Advanced Diagnostics†measurement function to save all data related to the sensor and process and display it in detail on the transmitter's graphical interface. This ensures that the measurement points are continually optimized because all important situations can be predicted and corrective actions taken early before production interruptions. For example, monitoring pH is critical for pH measurement. The ISM provides online glass impedance and reference monitoring. These data are graphically summarized on the sensor grid map and displayed on the transmitter (Figure 1). In the event that either or both of the impedance readings deviate too far from the center point of the network diagram, an impending failure is indicated, which can be replaced before the sensor fails.
Figure 1: Visual Reference System Monitoring by Sensor Performance Grid Diagram to Determine Sensor Dissipation A diagnostic parameter called “sensor wear level†can indicate the degree of change in the condition of a sensor used in a process (Figure 2). Taking the above impedance example as an example, it is possible to replace a sensor with a high degree of loss before it fails during operation, which can reduce the number of accidental interruptions. The maximum zui loss allowed for each measurement point can be individually adjusted to adjust to the level of confidence required for the process. In this way, maintenance strategies can be changed from passive, expensive and unpredictable workflows to fully proactive optimization processes. This is an example of continuous improvement and an aspect of the PAT action plan.
Figure 2: Part of the function of actively maintaining the sensor wear level parameter through the sensor wear level monitor is to monitor the CIP and SIP cycle frequencies. These are critical for proper functioning of pH and dissolved oxygen sensors during batch processes; however, they can adversely affect the slope of the sensor, resulting in improper measurement and premature sensor failure. To solve this problem, plant operators typically manually record the historical data of the sensor and develop a maintenance plan accordingly. The ISM sensor has a built-in CIP and SIP counter that detects when the sensor is used for thermal cycling. This data is stored in the embedded chip and then automatically uploaded to the transmitter. An alarm will be issued when the set number of cycles of zui is exceeded. This avoids the use of sensors that are likely to fail during the process.
The iSense Asset Kit is digitally signalable from the ISM sensor, so it can be connected to a PC or laptop via the USB port. This allows the sensor to communicate with the METTLER TOLEDO iSenseAssetSuite software, which provides different analysis, calibration and documentation tools. The key performance meter allows you to evaluate the condition of the ISM sensor at a glance without the need for a transmitter. One of the more useful features of the iSense software is the ability to calibrate the sensor from a PC/laptop. Since accurate pre-calibration in the laboratory results in superior performance in field applications, this is a huge advantage for large bioreactors, further enabling PAT targets.
Optical Oxygen Sensor During the fermentation process, the gas supply and agitation speed are adjusted according to the measured dissolved oxygen concentration value, thereby providing a good growth environment for the microorganism. Mammalian cell culture is increasingly used in the pharmaceutical industry, but mammalian cell culture is more sensitive to environmental changes than bacterial culture, and its growth rate is rather slow. In the full five-week batch production, the optical oxygen sensor fully proves its strength, that is, only a slight drift occurs during a long period of time. Stable measurements ensure batch consistency, which is another goal of PAT while maintaining a good growth environment. METTLER TOLEDO's new optical oxygen sensors are used in small, high pressure heated bioreactors and large production scale reactors.
iSenseISMAssetSuite
The built-in ISM technology in the sensor has a “plug and measure†function that ensures fast start-up and provides advanced diagnostics as described above. The ISM can help determine if the sensor is safe to use again in the next batch, or if maintenance is required (such as membrane replacement). In addition, optical sensors have good availability because they do not require polarization operations compared to polarographic sensors.
The core of the optical sensor is an oxygen sensitive layer containing immobilized label molecules. They absorb light from the light-emitting diodes and are capable of releasing energy at different wavelengths of light (fluorescence). Fluorescence depends on the amount of oxygen in the environment of the labeled molecule. This effect can be used to determine the oxygen concentration in the sample medium.
The measurement point verification ISM verification kit ensures that the measurement points can be verified without the use of sensors in accordance with GMP regulations. A system of five devices can simulate two fixed values ​​at different temperatures and different error conditions. It also verifies important ISM parameters such as SIP/CIP counters and dynamic life indicator.
Turbidity Sensor The online turbidity sensor provides real-time readings of the amount of light scattered by the cell suspension. This is because the turbidity of the cell suspension is directly related to the number of cells and is highly correlated with the optical density measurement. Knowing turbidity means that microbial activity in continuous culture can be controlled by adjusting the addition of nutrients and the rate of removal of the bioreactor medium. If this activity is copied into this process, the online turbidity measurement is also consistent with the PAT target.
Conclusion The recommendations in the PAT Action Plan are only recommendations, not rules. However, this does not mean that the pharmaceutical industry should continue to treat the new procedures reluctantly before the relevant regulations are introduced.
As shown above, the use of METTLER TOLEDO process analysis sensors with ISM technology ensures a better understanding of bioprocess and online monitoring, which is essential for feedback control and ensuring consistent quality. The ability to be compatible with PAT is inextricably linked to understanding and using the data provided by METTLER TOLEDO technology. In addition, ISM sensors help improve batch quality, reduce unplanned downtime, and reduce maintenance burden, all in line with the PAT Action Plan.
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