The biopharmaceutical industry has been growing steadily, driven by the development of new modalities and biomanufacturing technologies. Traditional bioprocessing methods, while effective, are facing significant challenges as the complexity and diversity of biopharma pipelines increase. This has led to the adoption of process intensification strategies, including continuous manufacturing and perfusion technologies. These advanced methodologies promise to revolutionize upstream bioproduction, offering higher productivity, economic efficiency, and sustainability.
The Steady Growth of the Biopharma Industry
The biopharma market is expanding at a significant compound annual growth rate (CAGR) of 8.5%, with projections reaching $1,183.72 billion by 2032. This growth is largely driven by the development of new therapeutic modalities such as antibody-drug conjugates, bispecific proteins, and cell and gene therapies. These new modalities add to the complexity and diversity of biopharma pipelines, necessitating innovative manufacturing solutions to meet the rising demand.
In this evolving landscape, many biomanufacturers are recognizing the limitations of traditional fed-batch (TFB) processes, which, despite improvements in cell culture media and feed strategies, still face inherent constraints. These include large bioreactor volumes, fixed culture durations, and significant changeover times, which can limit productivity and flexibility.
Challenges with Traditional TFB Bioprocessing
Traditional fed-batch bioprocessing has served as the backbone of biologics production for decades. However, it comes with several limitations that hinder its efficiency. For instance, TFB processes require large bioreactor volumes and have fixed culture durations, which can lead to substantial changeover times between production runs.
While advancements in cell culture media and feed strategies have somewhat improved TFB productivity and yields, these enhancements are not enough to overcome the fundamental constraints of the process. Large-scale operations especially find these limitations problematic, as they translate to higher operational costs and lower flexibility in manufacturing.
Embracing Process Intensification
Process intensification offers a transformative approach to biomanufacturing by enabling continuous manufacturing methods. Techniques such as N-1 intensification and intensified fed-batch are made possible through perfusion technologies like alternating tangential flow (ATF) and tangential flow depth filtration (TFDF). These methods stand out for their ability to maintain high cell densities and consistent product quality.
Perfusion cell culture, for example, continuously removes spent media while adding fresh media, keeping cells in a perpetual growth phase. This allows for extended production durations, higher cell densities, and more stable product quality, addressing many of the limitations faced by traditional fed-batch processes.
Benefits of Process Intensification
The shift to process intensification brings numerous advantages. Firstly, it enhances productivity by allowing higher cell densities and volumetric productivity. This is achieved by maintaining cells in a continuous growth phase, which can sustain high productivity levels over extended periods.
Economic benefits are also significant, as process intensification reduces the physical footprint of manufacturing facilities. Smaller and fewer bioreactors are needed, leading to lower costs for goods and more efficient use of space. Additionally, process intensification aligns well with sustainability goals, especially when integrated with single-use technologies, further reducing the environmental impact of biomanufacturing.
Implementation Considerations
Transitioning from TFB to intensified processes involves significant investment. This includes capital expenditures for new equipment, time for training personnel, and advances in control technologies to manage the more complex processes. Regulatory hurdles also exist, as process intensification often requires thorough process characterization and sometimes even clinical studies, given its classification as a new technology.
To facilitate smoother adoption, robust and scalable cell retention devices paired with automated controllers are essential. These tools help ensure seamless integration into existing biomanufacturing workflows, minimizing disruptions and optimizing performance from the outset.
Case Study: Roche’s Success with Perfusion Technology
Roche’s biomanufacturing transformation through process intensification offers a compelling case study. By adopting perfusion technology, Roche significantly enhanced its biomanufacturing efficiency. This strategic shift allowed the company to sell a 330,000 L facility to Lonza, reflecting a move towards smaller but more productive and flexible manufacturing sites.
The results were impressive, with Roche reporting substantial increases in titers—from an average of 1.5 g/L in 2015 to a projected 4.8 g/L. This transformation not only improved productivity but also allowed Roche to focus on smaller volume, higher potency new molecular entities, aligning its production closer to key markets.
The Shift to Continuous Manufacturing
The biopharmaceutical industry has experienced consistent growth, fueled by the emergence of new treatment modalities and advancements in biomanufacturing technologies. Traditional bioprocessing methods, though effective, are encountering considerable challenges as the complexity and diversity of biopharmaceutical pipelines expand. This increasing intricacy has necessitated the adoption of process intensification strategies, such as continuous manufacturing and perfusion technologies.
Continuous manufacturing, a shift from batch processing to an uninterrupted production flow, offers major advantages. It enhances productivity by allowing for ongoing operations, which can significantly reduce production time and costs. Additionally, it offers improved quality control, as continuous monitoring and adjustments can be made in real time, ensuring consistent product quality.
Perfusion technologies, another key strategy, involve the continuous feeding and removal of nutrients and waste in cell cultures, which maintains an optimal environment for cell growth and protein production. This leads to higher yields and more efficient use of resources.
Together, these advanced bioprocessing methodologies promise to transform upstream bioproduction. By embracing these innovations, the industry can achieve greater economic efficiency, increased sustainability, and high productivity. As these cutting-edge techniques become more widely adopted, they hold the potential to set new standards in biopharmaceutical manufacturing, paving the way for more effective and accessible therapies.
