Control charting each process step of your biologics process is a core activity for manufacturing managers that are serious about reducing process variability.
Sure, there's long-term process understanding gained from the folks in manufacturing sciences, but that work will be applied several campaigns from now.
What are the key performance indicators (KPIs) for my cell culture process today?
To answer this question, start with the purpose(s) of cell culture:
- Grow cells (increase cell population)
- Make product (secrete the active pharmaceutical ingredient)
Seed Fermentation (Grow Cells)
There are plenty of words that describe cell cultures whose purpose is to scale-up biomass; to wit, seed fermentation, inoculum cultures, inoc train etc. Whatever your terminology, the one measurement of seed fermentation success is growth rate (μ), which is constant in the exponent of the Arrhenius equation:
X = X0eμΔt
- X = current cell density
- X0 = initial cell density
- Δt = elapsed time since inoculation
For seed fermentation, the correct KPI is the final specific growth rate; which is the growth rate in the final 24-hours prior to transfer. The reason the final specific growth rate is the KPI is because the way seed fermentation ends is more important than how it starts.
Production Fermentation (Make Product)
The output of the Production Fermentor is drug substance; the more and the faster, the better. This why the logical KPI for Production Fermentation is Capacity-Based Volumetric Productivity.
A lot of folks look at culture titer as their performance metric. Mainly because it's easy. You ship those samples off to QC and after they run their validated tests, you get a number back.
- Culture Titer
- Mass of product per volume of culture (g/L culture)
The problem with using culture titer is that it does not take into account the rate of production of product. After all, if it took culture A takes ten days to make 2g/L and culture B takes 12 days to make the 2g/L, according to titer, they are equivalent, even though A was better. This is why we use volumetric productivity:
- Volumetric Productivity
- Titer/culture duration (g/L culture/day)
Culture volumetric productivity takes into account the rate of production pretty well, and in our example culture A's performance is 0.20g/L/day while culture B's performance is 0.17 g/L/day. But what of the differences between the actual amount of product manufactured? I can run a 2L miniferm and get 0.40g/L/day, but that isn't enough to supply the market. This is why bioreactory capacity must be included in the true KPI for production cultures.
- Capacity-based Volumetric Productivity
- Volumetric Productivity * L culture / L capacity (g/L capacity/day)
Capacity-based Volumetric Productivity is the Culture Volumetric Productivity multiplied by the percent of fermentor capacity-used, such that a filled fermentor scores higher than a half-full fermentor.
KPIs are generally not product-specific; instead, they are process class specific. For instance, all seed fermentation for CHO processes ought to have the same KPI.
Generally, KPIs are simple calculations derived from easily measured parameters such that the cost of producing the calculation is insignificant relative to the value it provides.
KPIs deliver significant value when they can be used to identify anomalous performance and actionable decisions made by Production/Manufacturing in order to amend the special cause variability observed.