PAT: Build Quality into Biopharmaceutical Processes with Real-Time Monitoring and Control

Scientist using Process Analytical Technology tools in a lab.

Process Analytical Technology (PAT) ensures quality in biopharmaceutical manufacturing by monitoring and controlling processes in real-time. It utilizes analytical tools to develop manufacturing processes that accommodate material and equipment variability. Once critical process parameters (CPPs) impacting critical quality attributes (CQAs) are identified, analytical methods are employed to monitor and control CPPs, maintaining them within the desired design space. This approach integrates quality by design (QbD) principles into the process rather than relying on product testing only in the end.

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PAT Enables the Facility of the Future

Incorporation of PAT into the manufacturing process helps establish the foundation for “bioprocessing 4.0” and the Facility of the Future, which is a complete digital transformation of biologics production using real-time monitoring, control systems and data analytics, providing greater process understanding, agility, flexibility, and improved quality assurance.

Analytical Insights Improve Process Understanding and Product Quality

More recently, PAT typically involves the use of chromatographic, spectroscopic and/or mass spectrometric sensors that are integrated into upstream and downstream unit operations. These technologies are used in-line, on-line, or at-line to enable real-time monitoring and control of the process.

Raman Spectroscopy as an Advanced PAT Tool for In-Line and Real-Time Monitoring of Bioprocesses

Raman spectroscopy is among the many tools used in PAT implementation. It enables the determination of chemical composition and molecular structure information in a non-destructive and reproducible manner, eliminating the risk of losing chemical information due to degradation, instability, or sample preparation. For example, the technique can be used to monitor cell culture CPPs such as glucose, lactate, cell density, and ammonium, as well as CQAs such as protein, glycosylation, and aggregates. Analysis is performed by insertion of a probe into the process along with other widely used sensors; as such, eliminates the need to collect samples to send to the quality control (QC) lab for analysis.

Compared with traditional off-line analytical methods such as a cell culture multitest analyzer, cell viability analyzer or HPLC, Raman spectroscopy offers clear advantages for both upstream (USP) and downstream (DSP) processes including:

Multi-attribute monitoring with a single probe
Complete chemical and biological information collected in a single spectrum
Access to real-time and in situ measurements
Non-destructive analysis
Easy implementation using an in-line probe

Scientist using a Raman PAT Platform in a lab.

ProCellics™ Raman Analyzer with Bio4C^® PAT Raman Software

An easy-to-use GMP PAT platform to monitor upstream and downstream processes in-line and in real-time, from process development to manufacturing.

Automated Aseptic Sampling as an Advanced PAT Tool for Near Real-Time, On-Line Access to Analytical Results

Automated Aseptic Sampling is particularly well-suited for the development of upstream processes (USP) as it offers significant advantages for the collection of cell culture samples, but the technique can also be used in downstream processing (DSP) and microbial fermentation.

The benefits of automated aseptic sampling to process development are significant. With the usage of this PAT technique, a sample is taken from its source without manual intervention and is transported directly for analysis or storage, maintaining a closed, sterile sampling environment. Automated aseptic sampling is modality-agnostic and modular by design, offering flexible and customizable solutions in its implementation. This technology can also be combined with other PAT technologies, such as Raman spectroscopy, for the improved calibration and validation of data-driven models.

Compared to current off-line sampling and analytical procedures, automated aseptic sampling provides clear advantages including:

Reduced contamination risk of the sample source
Increased frequency and acquisition of process-representative data points
Intensified turnaround times between experimentation and analytical action
Minimized number of invariabilities associated with off-sample hold times and testing
Decreased number of experiments required to make key process decisions

Scientist working with an automated sampling solution in a lab.

MAST^® Autosampling Solution

A versatile and modality-agnostic aseptic autosampling solution that ensures the direct collection, delivery, and analysis of samples from multiple sources without manual intervention, providing the user with more time to perform other value-added tasks.

Related Resources

Application Note: In-line Real-time Monitoring of CHO Cell Culture Process Parameters Using Raman Spectroscopy
Cell culture processes are complex and highly variable and yet only a handful of key parameters such as temperature, pH, and dissolved oxygen (DO) are typically controlled in real time.
Application Note: Implementation of Raman Spectroscopy for In-line Monitoring of CPPs of CHO Cell Perfusion Cultures
This application note introduces a case study for the implementation of a Raman spectroscopy soft-sensor for in-line and real-time monitoring of critical process parameters (CPP) in mammalian perfusion cell cultures.
Application Note: Seamless Integration of Glucose Control Using Raman Spectroscopy in CHO Cell Cultures
Process analytical technology (PAT) and quality by design (QbD) are used in the biopharmaceutical industry to ensure quality is designed into a process and to achieve innovative quality improvements.
Article: Influence of Cell Specific Parameters in a Dielectric Spectroscopy Conversion Model Used to Monitor Viable Cell Density in Bioreactors
In the biopharmaceutical industry, the use of mammalian cells to produce therapeutic proteins is becoming increasingly widespread. Monitoring of these cultures via different analysis techniques is essential to ensure a good quality product while respecting good manufacturing practice (GMP) regulations.