Achieving Consistent Performance by Managing Raw Material Variability Through Predictive Modeling

The past 30 years have brought significant progress in the design and manufacture of cell culture media as well as in the types of components used. With these advances, the biopharmaceutical industry improved its processes — from producing just a few milligrams of product per liter of culture to ≥10 g/L. Since the early days of microbiology, peptones have been used widely as a basic ingredient of microbial media. In the 1990s, peptones were introduced as a substitute for serum to achieve high expression titers (3–6 g/L).

That progress was led by two essential forces: the need and desire to reduce the risk of adventitious agents (e.g., removal of sera due to spongiform encephalopathy contaminations in the 1990s) and to achieve better process control for higher product quality, safety, and efficacy. All this was in the spirit of the quality by design (QbD) initiative led by the US Food and Drug Administration (FDA).

Major Drivers in Cell Culture: The first important cell culture parameter is the cell line itself: how it is designed, the nature of the expression system, and cell-line stability — all of which will influence process variability. The second driver encompasses process parameters for growing cells and controlling bioreactors. The third is the cell culture medium and all components and supplements used. These are essential to producing high-quality proteins that will be safe and efficacious. Here, we focus on process variability related to both the medium itself and components or supplements within it.

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