Advances in cell biology and associated technologies — from genetic engineering and nanotechnology to automation and data management — are changing the face of cell-line development in the biopharmaceutical industry. Seeing what’s possible, regulators are asking for more precision and better documentation on production cell lines than ever before. With an ever-intensifying desire for lowering the costs of development and manufacturing while speeding the progress of every biological candidate to market (or failure), companies are making new demands on their cell-line development groups to bring forth powerful, stable, high-expressing, and optimized cell banks as soon as possible. This featured report reviews the current state of the art of cell-line development, reports on recent discussions among experts in the field, and includes one specific case study illustrating some of the advancements being made.
Science Driving Technology: Cell Line Development and Engineering 2018
Cell-line development engineers in the biopharmaceutical industry must juggle several, sometimes contradictory priorities. They seek to present their bioprocessing colleagues with a master cell line that can express a reproducibly high-quality protein product at titers and growth concentrations that will be high enough for manufacturing efficiency — and without those parameters degrading over time. Meanwhile, these scientists have their own budgetary concerns and efficiencies to consider. Representing the first step in the bioprocess, they face regulatory scrutiny under the 21st-century risk-management paradigm. In turn, they make demands on the suppliers of instrumentation that they use. Modern cell-line developers are asking, “Can we engineer our cell lines to obtain good productivity and genetic stability without having to screen hundreds of thousands of clones? What properties are best to screen for? And how important is clonality, anyway?” Seeking answers, the senior technical editor attended the Knect365’s Cell Line Development and Engineering conference in San Francisco this summer — and she reports on that meeting here.
Myths, Risks, and Best Practices: Production Cell Line Development and Control of Product Consistency During Cell Cultivation
Barry Cherney, Dieter Schmalzing, Steffen Gross, Juhong Liu, and Christopher Frye
Health authorities are requesting substantial detail from sponsors regarding practices used to generate production cell lines for recombinant DNA-(rDNA) derived biopharmaceuticals as well as the information on the clonality of master cell banks and control strategies to minimize genetic heterogeneity. These requests have been triggered by reports indicating “non-clonality” for certain production cell lines. The overarching objective of this January 2017 strategy forum was to define the myths and risks to cell line development and product quality associated with cell cultivation and to identify current best practices to ensure that regulatory expectations are met when assessing and assuring the appropriateness of cell lines used for production of biotechnology products during development and commercialization. This article explores considerations for the development of production cell lines including
- The choice of expression system
- Strategies to minimize genetic heterogeneity of production cells
- The characterization of cell population genetic heterogeneity and potential approaches to improve cell line performance through host engineering
- Assurance of consistent production of the desired product
- Approaches to ensuring appropriate control of product quality throughout the cell culture process including advancements in analytical control strategies
- Strategies to accelerate early product development though the use of pool clones
- Lifecycle management of production cells
Rapid Generation of High-Producing Clonal Cell Lines
Thomas Kelly, Angela M. Tuckowski, and Kevin D. Smith
The Cyto-Mine system from Sphere Fluidics Ltd. (Cambridge, UK) is a microfluidic instrument designed for encapsulating single-cells in picodroplets with fluorescence resonance energy transfer (FRET) assay–based productivity screening in a single-use cartridge. Cell-line developers at Janssen R&D tested the instrument and method in both monoclonal antibody (MAb) and non-MAb projects. As the authors report here, they found that it can generate cell lines with high productivity, high viability, and a high assurance of clonality after just a single round of screening — all in shorter timelines than were previously possible.