Challenges in Recombinant Protein Harvest Clarification
Monoclonal antibody (mAb) therapies have a rich history that spans more than three decades; with more than 100 treatments currently available and many others in the pipeline. Recent technological advancements have unlocked the tremendous potential of mAb therapies in treating various severe diseases ranging from malignant cancers to autoimmune disorders. However, there is a pressing need to reduce costs and enhance production yields to ensure these crucial, life-saving treatments are more widely available. Traditionally, mAb manufacturing processes have been costly and complex. To satisfy the growing demand, it’s critical to increase production capacity, but this task does not come free of new challenges.
To start with, one notable challenge is the inconsistency between early laboratory processes, pilot processes, and commercial manufacturing. The shift from discovery to laboratory scale and then on to commercial manufacturing is anything but straightforward. It entails a multifaceted operation that can be both expensive and time-consuming.
The irregularities in scaling up arise from variations in purification technologies used at each scale, resulting in disparities in the impurity profile that must be addressed by downstream processes. For example, the performance of centrifugation in terms of particle removal and cell shear in small batch centrifuges is very different from the continuous centrifuges used at manufacturing scale. Scalability issues can trigger a host of problems, including cell culture fluid instability, poor product quality (due to the release of degradative enzymes resulting from cell shear), and downstream processes that struggle with variations in impurity profiles.
In addition to scalability, the pursuit of process intensification presents its own set of challenges. Process intensification aims to enhance production efficiency and reduce costs. By boosting productivity, manufacturing costs can be lowered, thereby expanding access to biotherapeutics for patients grappling with serious and chronic diseases. This approach also holds the potential to advance sustainability. As the pharmaceutical industry faces scrutiny over its environmental footprint, process intensification offers an opportunity to decrease the consumption of raw materials and reduce energy usage per unit of product.
However, intensifying upstream processes can lead to bottlenecks in harvest clarification, posing difficulties for biomanufacturers. To enhance bioreactor productivity, either the specific productivity of cells or the cell density per unit volume needs to be increased. Yet, a higher cell density results in an increase in solids that need to be removed during clarification, as well as elevated soluble impurity levels. These factors place a greater burden on downstream processes and reduce the efficiency of clarification, capture, and polishing stages. As a result, the product yield decreases, and overall manufacturing costs rise. Additionally, the composition of harvest cultures can vary significantly depending on the cell line, culture conditions, and upstream processing steps.
Current and traditional clarification technologies can fall short when faced with the challenges highlighted above. The primary objective of harvest and clarification processes is to eliminate cells and debris from the cell culture fluid, retaining only the necessary materials while removing the rest. The goal is to obtain material suitable for application in downstream chromatography columns. When considering clarification methods, techniques based on size and density, such as centrifugation and depth filtration, perform less effectively as cell density increases. Furthermore, traditional clarification processes typically involve multiple stages, and methods like centrifugation and depth filtration can damage cells, leading to an increased amount of impurities in downstream processes and a decline in product quality.
Overcoming these challenges calls for a multidisciplinary approach, innovation, optimization, and robust technologies that are:
Versatile to handle harvest cultures with various densities and viabilities
Consistent in their performance across scales
Capable of streamlining and intensifying clarification steps
Ultimately, these technologies should also strike a balance between productivity and selectivity. This ensures that the desired mAbs are effectively separated and purified while minimizing the presence of impurities.
To learn more about why traditional harvest clarification methods are inefficient and how a revolutionary new technology can change the future of biopharma manufacturing, download a recently released white paper.
