How CDMOs Solve Cell Line Development Challenges
Cell line development plays a pivotal role in advancing medical research and the production of biologic medicines. Through cultivating cells in a controlled environment, scientists can produce biologics, including antibodies and vaccines, that treat conditions ranging from cancer to COVID-19. More and more, contract development and manufacturing organizations (CDMOs) — companies that partner with drugmakers to develop and manufacture biologics — spearhead cell line development efforts.
Yet, despite a series of technological advancements that have enabled huge progress in scientists’ ability to edit and culture productive cells in the lab, there remain a series of obstacles to overcome. These include ensuring the robustness and stability of the cell lines, meeting the requisite yield targets, and abiding by stringent regulatory frameworks.
“Ultimately, only a few of the numerous companies that attempted to develop and commercialize COVID-19 vaccines were successful, despite many such entities investing significant resources. This is because CLD [cell line development] remains a significant challenge to biopharma, comprising complex processes that require scrupulous attention to conditions,” writes Daniel Buckley, lead scientist at CDMO Samsung Biologics, in a recent white paper.
“CLD timelines, product quality, and drug stability continue to impose difficult bottlenecks, but those hurdles can be overcome through the early-stage development and application of high-throughput analytic methods. The data gleaned can be used to make informed decisions and to optimize resources, resulting in a more efficient and successful CLD process. Often, a CDMO partner is able to drive this effort forward, drawing from previous experiences.”
High-Throughput Screening
High-throughput screening has become an essential method for CDMOs navigating the difficulties of finding the perfect cell line for a given biologic. Using automated systems, developers are now capable of quickly analyzing thousands of cell cultures and identifying those with the most promising attributes for further development. This approach both accelerates the development timeline and enhances the likelihood of isolating cell lines that will meet rigorous production and quality benchmarks.
HTS is an automated sifting process. It requires using either chemical or genetic methods to test the effectiveness of a cell in producing the antibodies or other proteins needed for a given therapeutic application. Chemical methods introduce various substances to interact with the biological target to study its behavior or effectiveness as a therapeutic target, while genetic methods involve manipulating or analyzing the genes associated with the biological target to understand its function, therapeutic potential, and yield. Both methods aim to validate the suitability and stability of a cell that could produce a therapeutic protein. The goal is to identify cells that will produce that protein efficiently without sacrificing quality.
“Samsung Biologics uses high-throughput methodologies, exposing each molecule to different stresses commonly encountered during process or storage,” says Buckley.
“The methodologies applied are well known in the industry and have been the topic of numerous publications, providing evidence that some of the outputs can help reduce risk during early-stage development. The analytical results from this developability assessment are evaluated as a whole and then compared against the wealth of internal data within Samsung Biologics and/or against marketed products. This enables a basic classification of a molecule relevant to its potential for development success.”
CHO Cell Lines
The choice of cell line is paramount, and Chinese hamster ovary cell lines are often the preferred cell type for CDMOs. CHO cells are adept at expressing proteins that are similar to those produced by human cells, and they’re more amenable to genetic manipulation. Moreover, the extensive historical data concerning their use and the relative ease of scaling up production make CHO cells a favored choice among CDMOs.
“When developing and manufacturing biologics, several types of expression host systems besides mammalian cell lines could be used, including bacterial or fungal cells. However, their potential for success in CLD and production of complex biologics like bispecific antibodies or mAbs is often not as high relative to Chinese hamster ovary (CHO) cell line platforms,” according to an article by Drug Target Review.
“Mammalian cells provide unique characteristics to the molecule, which cannot be mimicked by a lower level of organisms.”
The article lists glycosylation (adding a coat of sugar to proteins to ensure proper function), protein folding and assembly, and bond formation as key advantages of CHOs over non-mammalian cell lines.
CDMO Strategies
Apart from HTS and leveraging CHO cell lines, CDMOs employ a suite of strategies to surmount the challenges of cell line development. These include employing advanced analytical methods to monitor and optimize cell culture conditions, adopting quality by design principles to enhance process control, and staying abreast of the latest advancements in cell line development technologies.
CDMO partners are likely to become even more critical to the biopharma industry, enabling greater successes than the industry has seen to date,” says Buckley. “CDMOs will become more adept in identifying client molecules’ potential during the early stages of development, spurred by growing industry knowledge and experience.
