PAT is no Magic Trick: How On-Line Sensors Facilitate Help to Ensure “Quality by Design”

On-Line Sensors for PAT PAT is no Magic Trick: How On-Line Sensors Facilitate Help to Ensure “Quality by Design”

20.11.2019Author / Editor: Volker Kupitz* / Dominik Stephan

Keeping up with complexity — Bioprocesses are complex — thus, frequent measurement and data-driven real time process management are needed to keep complexity in check. The demand for a PAT that guarantees GMP and includes quality by design calls for specialised on-line sensor solutions. And recent technological developments are up to the task ...

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The FDA’s PAT framework calls for in-line process sensors that can move a measurement from manual sampling and laboratory instruments to automated control.
(Source: Hamilton; ©ra2 studio - stock.adobe.com; [M]Grimm)

Modern therapies of different diseases very often utilize drugs derived from living cells. However, manufacturing of these biopharmaceutical products is a complex process. One of the biggest challenges in biopharmaceutical production is to ensure reproducibility of the yield. The very nature of this challenge is rooted in the heterogeneity of a typical bioprocess, where minimal variations of the process conditions may lead to different yields.

It’s been 15 years since the FDA first released its Process Analytical Technology (PAT) initiative, challenging the biopharmaceutical market to adopt quality innovations through real-time monitoring and control of their processes.

Breaking new ground in bioprocessing: Viable cells behave like little capacitors. In an alternating electrical field their polarization and depolarization can be measured and the signal can be correlated to the bio-volume, resp. the viable cell density. Because only viable cells can be polarized, this method is insensitive to cell debris as well as to microcarriers. (©Paulista; ©gonin - stock.adobe.com; Hamilton [M]GötzelHorn)

To properly apply PAT, it is essential to move from the manual sampling and laboratory measurement procedures to automated control of critical process parameters. While the initiative has indeed spurred valuable new technologies, the journey to a fully quality-by-design future is still in its early stages with monitoring of many critical process parameters (or CPPs) having room for progress.

Critical Process Parameters for PAT

The most classical example of PAT applied to bioprocesses is the maintaining of a culture’s pH-value at a pre-defined set-point based on an in-situ electrochemical sensor signal. The signal is used to automatically regulate the addition of a base or acid (or the control of CO₂ for processes using mammalian cells).

Other CPPs that have been available for in-line measurement for some years are dissolved CO₂ and dissolved oxygen. Dissolved CO₂ is a parameter, which is monitored due to its influence on pH values in mammalian cells and the synthesis fatty acids. The currently available dissolved CO₂ process sensors are based on electrochemical principals. They are, however, affected by high maintenance costs to ensure an acceptable measurement accuracy.

Sensor specialist Hamilton is a pioneer in the optical sensor technology for the measurement and control of dissolved oxygen (DO). This technology has begun to supplant polarographic measurement and is now considered to be the state-of-the-art for the in-situ measurement of bioprocesses.

Gallery

The integrated micro-transmitter of “Incyte Arc” makes direct connection to the PCS easy. Advanced diagnostics and maintenance is possible using Hamilton's Arc Air software.

Hamilton's “Incyte” sensors enable real-time measurements of viable cell density in the bioreactor — a key performance indicator to properly apply PAT.

This year, Hamilton presented the new intelligent viable cell density sensor “Incyte Arc”.

Gallery with 6 images

In addition to the above mentioned parameters, proper monitoring of the nutrient (or substrates) concentration, as well as the measurement of secondary metabolites is important, especially for fed-batch and perfusion processes, as the feeding strategies can be controlled during the process.

In-line and on-line sensors are typically based on molecular spectroscopy technologies like Near-Infrared (NIR) and Raman. They are secondary measurement technologies, meaning measurement with off-line reference methods are required to calibrate them through use of statistical multi variate data analysis (MVDA).

Last but not least, also the temperature is a fundamental and well-controlled parameter. Bioprocess productions are typically monitored and controlled tightly to an optimal process specific temperature, including during sterilization cycles.

Monitoring these CPPs makes it possible also to maintain the related product Critical Quality Attributes (CQA) and process Key Performance Indicators (KPI) within the pre-defined limits.

Measuring KPI On-Line: A Matter of Sensors

Besides product quality and product titer, the total and viable cell density are key performance indicators, which, according to PAT, should be measured as often as possible. While measurements of product quality and titer today are still mostly performed at-line (due to limitations of currently available in-line technologies based on spectroscopic principles), there are now new technologies available to measure total and viable cell density continuously in-line.

How Intelligent Sensors Assure PAT

The FDA’s PAT framework calls for in-line process sensors that can move a measurement from manual sampling and laboratory instruments to automated control of CPPs and KPIs. This not only requires sensor technologies that can measure the individual parameters in-line while being able to withstand the Cleaning-In-Place (CIP) and Sterilization-In-Place (SIP) procedures.

It also requires sensor intelligence that leverages communication with the PCS and documentation needs. In the past 30 years, Hamilton Process Analytics has reshaped the monitoring landscape and, since 2009, brought the PAT framework closer to reality with the introduction of intelligent Arc sensors.

These Arc sensors “talk” directly to the PCS without the need for an additional transmitter. They not only send a compensated measurement value used to control processes, but also a host of diagnostic functionality on each sensor that is recorded automatically. The data recording and transmission are designed to meet or exceed FDA and GMP regulatory guidelines.

With the Arc Bluetooth package Hamilton created a monitoring and management solution fitted to the company’s intelligent sensor concepts. (Picture: Hamilton)

The information may be used immediately, as in the case of a process deviation, or for a future decision, such as when to calibrate or replace the sensor. This information is available through Hamilton’s Arc Air software on a mobile device (Android or iOS) or PC.

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Technology Focus

An Eye on Oxygen with Visiferm

The next generation of the popular “Visiferm” optical dissolved oxygen (oDO) sensors, “Visiferm mA”, greatly reduce calibration frequency and the risk of deviation while increasing the overall sensor lifetime at the same time. Currently, the standard optical dissolved oxygen best practice is to recalibrate the sensors after every run to prevent costly measurement deviations, which occur from batch to batch. However, each application is unique and individual factors on site, such as sensor aging, chemical attack, temperature and physical damage all contribute to a measurement’s relative error.

Algorithms to compensate for aging and temperature errors have therefore limited the utility. During the development of this next generation of Visiferm sensors, Hamilton engineers looked at ways to overcome the influence of SIP/CIP and photobleaching in order to reduce the frequency of calibration and unnecessary deviation reports. This required innovations in both, sensor and cap design. “Both key components have been enhanced for the most robust optical dissolved oxygen sensor ever on the market,” says Jahir Kololli, Product Manager at Hamilton Bonaduz.

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Technology Up-Close

Inside Incyte: Cell Density Measurement

With the new “Incyte Arc” sensor from Hamilton, the real-time measurement and control of the KPI viable cell density is now possible for the first time with the manufacturer’s comprehensive Arc intelligence. Marlene Frank, Product Manager at Hamilton Bonaduz, explains the innovation: “This sensor enables the proven high-fidelity permittivity measurements but is now paired with integrated microtransmitters that leverage Hamilton’s proven Arc technology, saving space and cost”. The microtransmitter amplifies the sensor signal for direct connection to the control system. Sensor configuration can be done either via USB or wireless Bluetooth. “This sensor simplifies process control and also reduces maintenance efforts to a minimum,” says Marlene Frank.

Where we’re going

Recent technological advances were leveraged toward the development of intelligent sensors. Hamilton specifically developed the Arc intelligent sensor family in order to overcome the greatest challenges in previous user processes. Costly, bulky transmitters were eliminated, documentation automated, data enriched, and calibration simplified to vastly reduce the operational cost and effort and increase security. Despite all of these advances, there are always hurdles to overcome. PAT encourages more and more data acquisition, and technology will need to continue to advance for operators to acquire, maintain, and use this influx of data.

Control and Automation at Achema 2015

Ultrasonic level switch (left) and thermal Level Switch by Magnetrol.

Separation layer messurement by Aquasant-mt Switzerland.

PH-sensor for cell cultures (left) and oxygen senosr for Fermentation processes by Hamilton.

The modular process coupling of the USG 20 covers basically all common couplings.

Gallery with 15 images

Hamilton is continually working on ways to simplify PAT compliance, from introducing new measurement parameters to progressing data management. Integration with cloud computing and Internet of Things (IoT) services will be the future of further simplifying the lives of plant operators and technicians. In the smart factory of the future, where so much is measured and documented, old data handling systems like those using the 4-20 mA protocol will not be able to keep up. The Ethernet protocol will be required to handle the rich data needed for modern processes. With more and more data available, a variety of new and retrospective analyses will be possible and could yield continuous improvement and new ideas for improving batch quality.

* * The author is Marketing Communication Manager at Hamilton Bonaduz, Planegg/Germany.

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