A central pillar of the biotechnology and pharmaceutical industries continues to be the development of biological drug products manufactured from engineered non-mammalian cells and mammalian cell lines or human derived cell lines. Cell line development has emerged as a cornerstone in the biopharmaceutical industry, significantly influencing the speed, quality, and efficiency of therapeutic protein production. Regulatory flexibility regarding cell line selection for biosimilars has spurred innovation in this area. Modern advancements, including high-throughput screening, single-cell cloning, and genome editing, have accelerated development timelines while ensuring product purity and potency. The industry is expanding beyond traditional CHO cell lines to explore diverse host systems, each offering unique advantages. Comprehensive cell line characterization, enabled by advanced analytical tools, is crucial for maintaining product quality and regulatory compliance. As the industry transitions towards continuous processing, cell line robustness becomes paramount. Ultimately, these advancements are driving the development of superior biotherapeutics, addressing unmet medical needs, and shaping the future of the industry.[1]
In the guidance document ‘Scientific Considerations in demonstrating biosimilarity to a reference product’ dated 28 April 2015, FDA states that “By contrast, the manufacturer of a proposed product is likely to have a different manufacturing process (e.g., different cell line, raw materials, equipment, processes, process controls, and acceptance criteria) from that of the reference product and no direct knowledge of the manufacturing process for the reference product.” This goes on to say that the sponsor of a biosimilar program might not have knowledge about the cell line used by the manufacturer of the reference product and hence need not use the same cell line, as long as safety, purity and efficacy of the proposed biosimilar is comparable with the reference product. In a nutshell, the sponsors of biosimilar programs can consider using a host cell line different from what is used by the manufacturer of the reference product provided the host cell has traceable clean history, demonstrated safety in humans and provides advantages over what is used for manufacturing the reference product. Innovative advancements in cell line development have revolutionized the biopharmaceutical landscape. This crucial process involves creating cell lines that produce therapeutic proteins and has witnessed an explosion of new technologies and methodologies. These developments promise to accelerate drug discovery and ensure that the produced biologics are of superior quality and efficacy.[2]
In earlier times, bacterial expression systems, yeast expression systems (e.g. Saccharomyces cerevisiae and Pichia pastoris) achieve rapid cell growth and high-protein yields with straightforward production scalability and without the need for animal-derived growth factors. The key challenge associated with yeast expression systems is their production of high mannose residues within their expressed PTMs (50–200 vs three molecules in human cells, as part of either N- or O-linked glycan structures), which may confer a short half-life and render proteins less efficacious and even immunogenic in humans. The majority of currently licensed biotherapeutic products are produced in non-human mammalian expression systems, as these systems are able to produce PTMs that (outside of a human expression system) most closely resemble those in humans. These expression systems are used to produce mAbs, hormones, cytokines, enzymes and clotting factors.[3]
Human tissue plasminogen activator (TPA) was the first marketed biotherapeutic expressed in CHO cells and the CHO-DUXB11 (double knockout gene dihydrofolate reductase (DHFR) gene) line was used to produce hundreds of kilograms of protein. Human tissue plasminogen activator (tPA) is classified as a serine protease (enzymes that clea...
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