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

The ability to monitor biopharma processes in real time provides significant advantages in optimizing product quality with respect to multiple attributes.

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Released By MilliporeSigma

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.

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.

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 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 the insertion of a probe into the process along with other widely used sensors and 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 cell culture multitest analyzers, cell viability analyzers 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
Automated Aseptic Sampling is another PAT tool, 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 tools, such as Raman spectroscopy, for the improved calibration and validation of data-driven models.

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