Raman analytical monitoring of bioprocesses – a Process Analytical Technology (PAT) solution

by Delphine Simiand | September 20, 2021


Cell culture processes are complex and highly variable in nature and yet only a handful of key parameters such as temperature, pH, and dissolved oxygen (DO) are typically controlled in real-time. While the measurement and control of these parameters is necessary for successful bioprocess monitoring, they do not provide a direct indication of the culture’s content itself, but only rough assumptions on the culture’s true state and limited process and cell growth understanding. Critical process parameters (CPP) such as glucose, lactate or ammonium and key performance indicators (KPI) such as total cell density (TCD) and viable cell density (VCD) provide a direct indication of the culture’s content and state but are generally measured off-line and therefore, not in real-time. Similarly, mammalian cell culture feeding strategies lack real-time measurement and rely on daily manual sampling which increases the risk of contamination and batch failures.

Our new Raman PAT Platform provides a path forward. Based on Raman technology, specifically designed for the bioprocessing industry, it enables to perform in-line and real-time measurement of CPPs and CQAs. It therefore helps improve processes, save time and provide flexibility to operators, reduce the risk of contamination and batch failures, and even implement a nutrient control loop strategy, a first step towards automation.

But what exactly is Raman technology, and why is it particularly well adapted to bioprocess monitoring?

The Raman effect

Raman technology in a non-linear process consisting of the exchange of energy between the optical wave and the molecular vibration of a substance.

For example, water (H2O) has three different molecular vibrations (bend, symmetric stretch, and asymmetric stretch) and one response of the molecular bond to excitation by a laser is the Raman signal. As the water molecule has three vibrations, there are three different Raman signals.

A Raman spectrum is a graph of Raman signal intensity as a function of the Raman shifts. For a water molecule, each of the three Raman signals correspond to a peak in the water Raman spectrum. A Raman spectrum can be likened to a molecular fingerprint.

Raman in bioprocessing

Raman technology is fully adapted for measurement in aqueous medium with no impact of water. It is non-destructive and can provide simultaneous, real-time monitoring of several process parameters and quality attributes including total cell density (TCD) and viable cell density (VCD) and concentration of glucose, lactate, ammonium, glutamine, amino acids and proteins. The resulting Raman spectra are a collection of molecular fingerprints analyzed with the use of multivariate analysis tools such as chemometric modeling. Chemometrics is used to build multivariate models of spectral variation and sample characteristics with off-line measurement in a calibration set.

Interested in monitoring your upstream cell cultures in real time? Discover how ProCellics™ Raman Analyzer with Bio4C™ PAT Raman Software, new Process Analytical Technology can help. 

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