The FDA’s 2004 guidance on process analytic technology (PAT) created a sub-industry focused on “reducing production cycle times by using on-, in-, and/or at-line measurements and controls.” GEN reported back in 2006 (and again in 2011) that adoption of PAT was proceeding slowly. That is still true, but PAT has received a shot in the arm through its Biopharma 4.0 connection.

Of the FDA’s PAT designations, in-line is by far the most difficult to implement, and unsurprisingly one cited most often as a 4.0 enabler. The challenge when sampling doesn’t occur is trusting that measurements of some surrogate quantity represents the actual process parameter under consideration. As a side note, relevant instrumentation should be compatible with single-use bioprocessing.

Unlike pH and dissolved gases, biomass sensing is difficult to “PAT-ify” because it involves several manual steps which, even when executed perfectly, “provide only a reactionary window into the past.” By avoiding sampling entirely, capacitance-based biomass sensors operate essentially in real time and are compatible with most cell lines, bioreactors, and bioprocesses.

Capacitive biomass measurements aren’t new, having been described for microbial fermentations as early as 1992. Many companies sell capacitive biomass sensors today, for example Hamilton’s products for viable cell density and total cells, Lion Precision’s linear displacement sensors, a screening capacitive model suitable for classifying new cultures, more-or-less standard optical density/turbidity probes by Solida Biotech, and many others.

In March 2021, Aber Instruments introduced the Futura neotf capacitance-based single-use biomass sensor which allow what Aber calls “process fingerprinting” for on-line monitoring and control of cell cultures to support biomanufacturing.

Futura’s fingerprints help manufacturers maintain critical process parameters and quality attributes from batch to batch by rapidly identifying parameters that fall out-of-specification. Fingerprints may also be applied to advanced control of, for example, optimum cell harvest or virus infection times.

“This fingerprint becomes the signature of the process,” says Aditya Bhat, VP, technology at Aber Instruments. “The capacitance trend for the process under investigation can then be compared, in real time, to the historical capacitance fingerprint. If the ongoing process trend is seen to deviate from the historical fingerprint, then this can be a call for troubleshooting the process, which can either lead to process recovery or stoppage. By comparison, offline methods are incapable of real-time troubleshooting, and the level of detail is also insufficient for them to be used for process fingerprinting.”

Other methods, says Bhat, fall short when cells lose viability. With capacitance sensors, one can observe different growth and death phases in real time. Capacitance is a direct measurement: You know exactly what is being measured, namely charge buildup around live cell membranes.”