THE UPSTREAM PROCESS
BioPharm: Can you start by walking us through a brief description of what's involved in a typical upstream process for manufacturing a biologic-based product?Nelligan: A typical process lasts approximately 40 days, so it's quite lengthy. The first 21 to 25 days involves growing the cells. Typically, each batch starts from cells stored in an ampoule. The cells are kept viable by being stored in liquid nitrogen in the laboratory. These cells are laid down by the research teams who first developed the cells and processes for later production. For commercial production purposes, one needs to use a vessel in a size ranging from a 1000 L to 10,000 L. This means the starter culture must be grown in a series of passages before inoculating these large production vessels.
Typically, the process begins with a few milliliters of cells in an ampoule growing up over 21 days to eventually inoculate a 1000-L or 2000-L production vessel. These cells last approximately 12 days in the production vessel, their metabolism being switched from growth to a production state by computer control of conditions. It is in this production stage that the cells make the targeted product (i.e., the drug substance) until it's ready to be harvested. At this point, one may have a few kilograms of monoclonal antibody (mAb), for example.
BioPharm: When scaling up from a laboratory process to a production process, as you've described here, what considerations does the manufacturer need to keep in mind when developing an overall biologic process? In other words, how can a team best prepare for the scale-up stage?
Nelligan: The process must be robust, first and foremost. Animal cells are very complex. The industry still struggles with identifying the areas of variability. Even though computer-controlled vessels are used to control the cells' metabolism very tightly, the quality of the product needs to be carefully checked before being dispositioned. One needs to keep in mind that mAbs are very powerful substances and over a thousand times more complex than the small-molecule chemical products produced by the pharmaceutical industry in the past. Sophisticated and state-of-the-art analytical techniques are therefore required to characterize such products. If the process is not robust and the drug substance product has not been fully characterized in the early development (or clinical trial) stages, undesired variability can arise when moving to large-scale manufacture.