Cell culture processes for monoclonal antibody production

Abstract

Animal cell culture technology has advanced significantly over the last few decades and is now generally considered a reliable, robust and relatively mature technology. A range of biotherapeutics are currently synthesized using cell culture methods in large scale manufacturing facilities that produce products for both commercial use and clinical studies. The robust implementation of this technology requires optimization of a number of variables, including 1) cell lines capable of synthesizing the required molecules at high productivities that ensure low operating cost; 2) culture media and bioreactor culture conditions that achieve both the requisite productivity and meet product quality specifications; 3) appropriate on-line and off-line sensors capable of providing information that enhances process knowledge; and 4) good understanding of culture performance at different scales to ensure smooth scale-up. Successful implementation also requires appropriate strategies for process development, scale-up and process characterization and validation that enable robust operation that is compliant with current regulations. This review provides an overview of the state-of-the art technology in key aspects of cell culture, e.g., engineering of highly productive cell lines and optimization of cell culture process conditions. We also summarize the current thinking on appropriate process development strategies and process advances that might affect process development.

Figure 1

96-well Elisa assay of clones from single and double selection. For each case, 72 clones were screened. [Notes: MTX, methotrexate; MSX, methionine sulphoximine].

Figure 2

Clinical and process development flowchart. [Notes: POC, proof of concept; IND, investigational new drug application; Tox, Toxicology; BLA, biologics license application; TT, technology transfer; cGMP MFG, current good manufacturing practices compliant manufacturing; PD, process development].

Figure 3

The antibody concentration profile shown for the same cell line, but grown with “platform” media, which will be applicable across multiple cell lines with minimal modifications and the “enhanced” media, that is specifically optimized for maximizing the volumetric productivity of this cell line.

Figure 4

Cell culture process operating parameters affect process performance and product quality.

Figure 5

A large-scale cell culture process steps and their key process performance parameters.