Upstream
The sector of upstream production continues to face demands for increased efficiency and output. Scalability is an ever-present goal in manufacturing processes as drug developers seek to increase expression titers, reduce process and facility footprints, and decrease overall cost of goods (CoG). The “Cell Culture and Upstream Processing” track at the 2024 BPI Conference focused primarily on methods that biomanufacturers are using to scale up to commercial production and increase product output without sacrificing quality or efficiency. Drug developers are committed to bringing products to patients quickly, safely, and cheaply. To achieve that goal, presenters said, developers must continue to find and overcome weaknesses within their manufacturing processes.
Scale-up requires consistent performance and product quality. Jianfa Ou of Bristol Myers Squibb noted how manufacturers must define scale-dependent parameters — such as oxygen supply, foam control, shear stress, and mixing — and then find ways to maintain such factors during scale-up to ensure high product quality and reduce variability between batches. Performance gaps between screening and productions phases must be assessed, and root causes of those gaps must be defined and addressed. Meanwhile, a speaker from Gilead reported on scale-down models for measuring upstream performance variance across manufacturing scales and facilities.
Digital-twin models can be used to optimize control strategies. For example, glucose feeding is a delicate process: Although frequent feed additions can prevent nutrient depletion and help sustain protein production in cell cultures, excessive feeding can raise levels of toxic by-products and bring contamination risks. As presented by Min-Cheol Kim of Sanofi, digital twins can be used to predict feed outcomes based on selected parameters, enabling refinements of such processes without wasting materials or time. Data-driven optimization can assist and inform throughout every stage of upstream production (e.g., to gain understanding of amino-acid limitations during perfusion). Process engineers — such as Sarah Harcum’s team at Clemson University in South Carolina — use such learning models to remove nutrient bottlenecks from production processes.
An increasing number of antibody–drug conjugates (ADCs) are in development for oncology indications. Kyle McHugh of Takeda discussed how process intensification can help to shorten investigational new drug (IND) timelines for ADCs. Each component of a conjugate product has its own good manufacturing practice (GMP) release point, and the regulatory path is lengthy for ADCs. Overlapping discovery stages with chemistry, manufacturing, and controls (CMC), however, can help companies make up time without risking quality.
As the biomanufacturing industry continues to improve its upstream processes, it helps to take a step back and assess how far bioprocessing has come. Ciaran Brady of Vertex Pharmaceuticals presented about “Lessons Learned During Casgevy,” including insights from the regulatory journey of the first approved therapy based on clustered regularly interspaced short palindromic repeats (CRISPR) technology and associated protein 9 (CRISPR–Cas9). Brady suggested how companies can improve their methods even after product approval. Increasingly robust manufacturing practices for cell and gene therapies (CGTs) must be implemented to meet global supply-chain demands in the future.
Addressing challenges like identifying high-performance media and optimizing scalable processes, Lonza CHO media portfolio, including TheraPRO®, streamlines media screening and optimization for commercially available CHO cell lines. Achieve high titer and superior scalability with our globally harmonized, regulatory-compliant manufacturing facilities, enabling a seamless transition from research to commercial manufacturing.
I am currently a Product Manager with Biosciences at Lonza for bioprocessing media focusing on protein based therapies. I have over 10 years of cell culture experience including diverse cell line growth, cell line development and cell culture media composition. After studying molecular biology for my BSc at Queen Mary, University of London and MSc at the London School of Hygiene and Tropical Medicine, my PhD set out to study the cell biology of infectious diseases, specifically bacterium Orientia tsustugamushi at the Open University/University of Oxford. I then completed my Post-Doc at Rutgers, the State University of NJ in the US.
