Cell line development plays a crucial role in biopharmaceutical manufacturing, enabling the production of recombinant proteins, monoclonal antibodies, and other biotherapeutic products. However, CLD often faces numerous challenges, ranging from genetic instability to low productivity and toxicology concerns. Addressing these challenges early in the development process is essential to ensure successful and efficient production of high-quality cell lines.
In a recent white paper, two scientists at contract development and manufacturing organization Samsung Biologics, Seahee Kim and Daniel Buckley, explained how early-stage assessment and management can help CDMOs overcome these challenges.
“CLD time lines, 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,” they write. “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.”
What Is Cell Line Development?
A cell line is a population of cells derived from a single parent cell that can replicate indefinitely and is commonly used in scientific research and biopharmaceutical manufacturing. Cell line development is a complex and iterative process that involves the selection and optimization of high-performing cell lines capable of producing desired biotherapeutic products.
However, various hurdles can impede the development process, including genetic instability, low expression levels, and lengthy timelines. Early-stage assessment and management serve as proactive measures to mitigate these challenges and streamline CLD.
How CDMOs Utilize Early-Stage Assessment
There are several steps to early-stage assessment of a cell line, and CDMOs with experience in CLD will carry out each based on data unique to the project in combination with lessons learned from prior successes in other projects.
Identifying a suitable clone with desired characteristics is a critical step. When a cell line is initially established, a single cell is isolated and allowed to divide and multiply, giving rise to a “clone” population of cells. Each cell within this population is genetically identical because they originate from the same parent cell and have undergone mitotic cell division. These cells are referred to as clones because they collectively exhibit similar genetic characteristics and physiological properties.
Early assessment of clones using high-throughput screening technologies allows for the identification of high-productivity clones early on, minimizing downstream bottlenecks. High-throughput analysis involves rapid and parallel assessment of a large number of cell line clones or samples to screen, evaluate, and select high-performing candidates based on desired characteristics. This approach is a cornerstone of Samsung Biologics’ strategy.
“While [biopharmaceutical companies] likely recognize the importance of early material assessment and ensuring quality from an early stage, they may lack the capital and/or testing expertise to help predict developability,” explain Kim and Buckley. “Combined with an optimized process, Samsung Biologics’ DEVELOPICK platform can provide biopharmas with the opportunity to check their material’s development potential in a project’s early stages. The platform is a risk-mitigation tool that provides rapid analysis of molecules, which aids in identifying those molecules with the greatest chance of success.”
Kim and Buckley also note that toxicology manufacturing is vital at this early stage. Toxicology manufacturing assesses the impact of a product on living systems, including cells, tissues, and animals, to ensure that it meets regulatory safety standards. In CLD, this involves the evaluation of the safety and potential toxicity of the cell lines themselves and the products they produce. This assessment is essential because any impurities, contaminants, or unwanted characteristics of the cell line or the biotherapeutic product can pose risks to patients.
“Sponsors typically want to execute tox experimentation as soon as possible because it is their first opportunity to observe their molecule in vivo. But CDMOs lacking experience and/or established early-stage analytical processes during CLD often encounter difficulties and delays attempting to reach tox manufacturing,” write Kim and Buckley.
“A ‘pool of top clones’ strategy is one method to accelerate the availability of toxicology drug substance material for regulatory filing-enabling studies. Selecting only the most promising clones for this pool is key to this strategy’s success. Samsung Biologics uses a combination of cell growth/productivity and product quality analysis, along with next-gen sequencing and mass spectroscopy, to verify the absence of sequence variants among clones for the pool.”
In addition, strategic genetic engineering techniques, including gene amplification and knockouts, can enhance cell line productivity and stability. Incorporating these techniques during early-stage development expedites the generation of high-performance cell lines.
Benefits of Early-Stage Assessment
Addressing challenges early in CLD enables CDMOs to get ahead of potential roadblocks that could cause costly delays in later stages. Proactive assessment minimizes process iterations, shortens time lines, and reduces overall development costs.
Early-stage characterization and optimization provide a better understanding of critical parameters, allowing for improved control over the cell line development process. This knowledge enhances process scalability and reproducibility, facilitating a seamless transition from development to commercial-scale manufacturing.
Successful cell line development requires a comprehensive approach that includes early-stage assessment and management. By proactively addressing challenges related to clone selection, toxicology manufacturing, and genetic stability, CDMOs can optimize their CLD process, leading to improved time lines, increased success rates, and enhanced process control.