How to Measure Cell Culture Productivity

by Oliver Yu

So I've written about key performance indicators (KPIs) for cell culture in the past. And the KPI depends on whether you're talking seed/inoculum vs. production culture.

Final Specific Growth Rate

To recap, if you're in charge of monitoring seed/inoculum cultures, your goal in life is to deliver a specific amount of cells in the growth phase; therefore, your goal is to have a high final specific growth rate.


Compute specific growth rate by taking the slope of the natural log of the biomass against time.

Culture Volumetric Productivity

If you're in charge of production culture you want to have as high a concentration (of product) in as short a time as possible. Therefore, you seek a high volumetric productivity, which is:

For lab- and pilot-scale operations, this KPI is just fine.

Capacity-based Volumetric Productivity

For large-scale, commercial cell culture, however, volumetric productivity of the culture misses the mark and here's why:

Suppose you had a 2.5g/L process and you were able to get that in 10 days. Your volumetric productivity is 0.25 g/L/day. If your working volume is 10,000L this means you have 2.5 kilos of product.

Well, if your bioreactor is a 10kL, then you're making as much product as possible. But if your bioreactor is a 12kL, then you're not using your capacity to the fullest. This is why a better metric is capacity-based volumetric productivity:

In situations where your plant is always running, there's another metric.

Plant-based Volumetric Productivity

Even though culture duration (harvest timestamp - inoculation timestamp) is the only period when the product is being produced, the total time consumed should include the time spent cleaning, sterilizing and prepping the bioreactor. The time spent turning a dirty bioreactor (from the last harvest) to a prepped bioreactor is called the turn time, and when you include that into the equation, you get a true measure for the productivity of your biologics manufacturing plant called plant-based volumetric productivity:

Summary

Plant-managers are fine knowing the final titer or just the total culture mass since titer is just a single number coming out of QC and culture mass is what you're accountable for.

But if your team of cell culture scientists/engineers in MSAT are interested in comparing cultures on an apples to apples basis, they had better be control charting volumetric productivities.