Small Bioprocess Monitoring Hits the Goldilocks Zone

Process analytical technology (PAT) bioprocess monitoring instruments generally are designed for large-scale processes, which leaves small-scale bioprocessing at a decided disadvantage. In the days of blockbuster therapeutics, that wouldn’t have mattered much. Today, however, process intensification and increasingly personalized therapies are decreasing batch sizes, so the lack of real-time PAT monitoring options for small-scale manufacturing is a growing concern.

That limitation is felt particularly in the paucity of in-line instrumentation to measure viable cell density, where biocapacitance probes are too large. Alternative, offline viable cell counting methods such as the trypan blue exclusion method limit real-time monitoring in small vessels and, according to a team of Swiss scientists, are impractical for small-scale bioprocessing.

The team led by Yves Mermoud, PhD, research scientist, Eastern Switzerland University of Applied Sciences (OST), and colleagues from OST and Zurich University of Applied Sciences is showing progress in remedying that situation with a viable cell density that appears to be neither too big nor too cumbersome but, as Goldilocks said, just right.

They recently reported on a proof-of-concept, miniature, viable cell density sensor that they tested against concentrations of Chinese hamster ovary (CHO) cells. This work is admittedly in its early stages, but it promises a PAT-compliant sensor for small volumes that currently lack good measurement options.

The miniature bioimpedance sensor they are developing has a 1 x 10 mm footprint at a 25 µL working volume. “Performance [is] close to conventional probes,” Mermoud and colleagues report.

A good starting point

The team measured electrical impedance from 10 kHz to 5 MHz, with an amplitude of 200 mV. The detection limit was approximately 0.5 × 10⁶ cells mL⁻¹. Deviations at the upper and lower limits were comparable to those of commercial probes, according to data the team presented at the recent Eurosensors 2026 meeting.

There, they reported a linear correlation when measuring the viable density of CHO cells and closely—but not perfectly—tracked reference cell counts. More specifically, Mermoud tells GEN, “Their measurements showed strong correlation with the reference cell counts (R² = 0.92), indicating that a linear relationship explained 92% of the observed variation.”

To create these miniaturized sensors, the researchers fabricated evaporated platinum thin-film electrodes onto a 100 mm fused silica wafer by photolithography. The wafer was cut into 15 x15 mm microchips that were connected to an impedance analyzer. Each chip features two microfluidic channels.

“The PAT microchip cell density sensor has already demonstrated continuous at-line monitoring in representative 14-day CHO fed-batch cultivations,” Mermoud says. “In these studies, cell suspension was circulated through an external demonstrator module housing the PAT microchip. Our focus now is on improving signal analysis to account for process-related changes in the culture medium over time.

“Going forward, we will package the PAT microchip as a standard insertion probe for direct inline deployment in the bioreactor and expand the data analytics with multivariate models that leverage the microchip’s multiple sensing modalities,” Mermoud elaborates.

“We are currently seeking industrial partners to support and accelerate this final translation into a commercial process sensor.”

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