Cell Line Development
Cell-line development (CLD) is a rapidly evolving field in which scientists are leveraging cutting-edge technologies in genetics, automation, and data science to drive improvements in speed, efficiency, and product quality. Case studies presented in the “Cell-Line Development and Engineering” track at BPI’s 2024 Conference showed how such innovations are transforming upstream bioprocess development by accelerating timelines while maintaining the highest standards of quality and regulatory compliance. The breadth of innovative approaches and technologies on display reflected the biopharmaceutical industry’s recent push toward increasingly efficient processes.
The power of advanced genetic-engineering techniques was a central focus. Clustered, regularly interspaced, short palindromic repeats (CRISPR) technology is feeding into CLD through ongoing explorations of its applications and future implications. However, as one presenter pointed out, ongoing discussions of CRISPR patent rights and licensing are complicating the landscape of innovation. Meanwhile, a number of different transposase/transposon platforms provide demonstrated means to enhance transgene-expression levels and modify cellular physiology.
High-throughput screening and automation have become vital to accelerating CLD timelines. Integration of automated systems for cell selection, imaging, and cultivation is increasingly widespread within the industry. Instruments such as the Berkeley Lights Beacon imager and Ambr microbioreator systems from Sartorius continue to be featured frequently across numerous presentations.
Data-driven approaches and digitalization are generating vast amounts of information that companies need to parse for informed decision-making. Biosensor technology is emerging as a promising tool for enhancing productivity. For example, one speaker showed how fluorescent biosensor proteins can be coexpressed alongside therapeutic molecules to aid in selection of high-producing cell lines. New imaging and monitoring technologies have eliminated the need for cell staining. Such innovations can provide for continuous monitoring of bioprocesses to give real-time insights into cell growth and metabolism.
As usual, most speakers reported working with Chinese hamster ovary (CHO) cell lines, the cornerstone of biopharmaceutical production. Strategies for developing high-producing CHO cells are being refined along with approaches to overcome common challenges of CHO-based manufacturing. However, other expression systems are becoming increasingly viable. One presentation highlighted a way to enhance the reliability of the baculovirus expression-vector system (BEVS) for use with a Spodoptera frugiperda cell line that’s free of Sf-rhabdovirus, a common contaminant of such cell lines.
Holistic strategy was a key theme across this year’s CLD track. Integration of multiple technologies — combining genetic engineering, automation, and data analysis to create comprehensive CLD solutions — helps to build “intelligent ecosystems” that span the biopharmaceutical-development spectrum from drug discovery through process engineering to chemistry, manufacturing, and controls (CMC) for regulatory submissions. Digitalization of cell-line assessment and selection is one aspect of such efforts as some companies implement data management, visualization dashboards, and machine-learning algorithms.
A number of speakers emphasized balancing acceleration of timelines against maintaining product quality and process robustness and phase-appropriate understanding of processes and products. Results of a BioPhorum survey — reported by Thomas Kelly of Johnson & Johnson Innovated Medicine — illustrate the value of shared learning and collaborative approaches in advancing the field while acknowledging the importance of tailoring strategies to the needs of specific product candidates.
Based on market feedback, the most important challenge companies face when adopting CRISPR technology for commercial cell line engineering is the complex landscape of intellectual property (IP). Multiple ownership of CRISPR/Cas9 patents has created uncertainty regarding commercial freedom to operate (FTO). This presentation will showcase how Demeetra has combined its own Cas-CLOVER IP with the CVC, key holders of foundational CRISPR IP. Our unique sublicenses enable clients to obtain straightforward commercial access with undeniable FTO, while maintaining industry-leading knockout and knock-in efficiencies.
As CEO, Jack is focused on providing partners with commercially applicable gene editing technologies through simple accessible licenses. Prior to Demeetra, he was at Hera BioLabs, where he successfully led a complete business pivot to spear-heading the first fully immunodeficient gene edited rat models for oncology xenografts. While serving as VP of Business Development at Transposagen, Jack was instrumental in laying the foundation for commercial applications of the piggyBac transposase, a widely adopted gene editing technology. Mr. Crawford holds a BS in Biochemistry from Virginia Tech and a Master's in Biotechnology from University of Pennsylvania.
Antibody production relies on a broad range of raw materials. Most of these raw materials are used in various industrial applications and their specifications have not been developed with antibody production in mind. Chemical or physical characteristics, contaminants and impurities may diverge between lots and can lead to variability in performance of these raw materials in antibody production, even though these raw materials work well in other applications. This leads to process inconsistencies, yield loss, and can even affect the characteristics and quality of the final drug product. The Biopharma industry has recognized the importance of raw material consistency and efforts have been made to better understand the requirements for raw materials in bioprocessing. Raw material suppliers are using the learnings of the Biopharma industry and started developing application-specific products for the biopharma industry, which reduce the risk of performance variations. One example is BASF’s Kolliphor® P188 Bio, which was developed to address performance variability in cell culture. We would like to share our learnings from developing raw materials with Biopharma in mind and give an outlook on how raw material suppliers can support the Biopharma industry to achieve more robust and efficient processes.
Jack Samuelian received his Ph.D. in Chemistry from Saint Louis University. His research was focused on RNA aptamers and their role in the origins of life as well as the discovery and use of DNA aptamers for illicit drug detection. Jack joined BASF in 2022 as has been working as a Scientist within the Biopharma Ingredients Technical Marketing team to help generate experimental data on existing products as well as collaborate with R&D in the development of new product. His primary focus is processing aids using in upstream and downstream applications.
