The Promise of Continuous Processing To Advance Biopharmaceutical Production

The biopharmaceutical industry has seen substantial growth in recent years, generating novel biotherapeutics and biosimilars at an unprecedented rate. One of the biggest challenges in the industry is to produce high-quality biologics in flexible volumes while reducing costs to improve access to potentially life-changing biological treatments. Manufacturers are, therefore, constantly seeking novel approaches to optimize their development and production processes to meet growing and diversifying demands. 

Batch and fed-batch systems have long been effective for biotherapeutic manufacturing, with advances pushing yields up to 10 g/l. However, traditional fed-batch manufacturing systems struggle to keep pace with increasing production demands.

In addition, dynamic conditions within the bioreactor can lead to an imbalance of nutrient supply and waste accumulation, resulting in incomplete glycosylation, compromised cell health and higher product degradation, ultimately affecting product quality. The low volumetric productivity of fed-batch biotherapeutic manufacturing also requires large facilities that increase production costs.

The shift to continuous manufacturing

Switching from traditional batch and fed-batch methods to a more resource-efficient, automated continuous manufacturing process offers biopharma companies a convenient solution to significantly improve their productivity and product quality.

In contrast to batch methods, continuous processing maintains stable conditions within the bioreactor, providing a constant supply of fresh nutrients and continual removal of waste to support high cell densities and extended growth phases. This leads to higher productivity – often significantly exceeding the limits of fed-batch systems – and enhances process efficiencies.

Simpler, more cost-effective media formulations can be used due to the ongoing turnover of media, ensuring overall process economics are improved. Furthermore, continuous manufacturing brings the added benefit of increased flexibility in biopharmaceutical manufacturing, as it enables production in smaller facilities that are amenable to modular design and more readily responsive to fluctuations in market demands.

Many companies are already capitalizing on these benefits and converting their fed-batch processes to continuous biomanufacturing during clinical development, allowing them to optimize production costs for the later stages of biopharmaceutical development and commercial manufacturing.

Continuous biomanufacturing can be either hybrid – semi-continuous – or fully end-to-end. Hybrid manufacturing combines both batch and continuous processes within a single production workflow. For example, upstream processes, product capture and viral inactivation may be run continuously, while subsequent polishing purification steps are batch, even if highly intensified.

Hybrid manufacturing is often applied during early-phase clinical manufacturing, when the priority for sponsors is generating material for toxicological studies and first-in-human clinical trials in the shortest possible time. A hybrid process can then be easily converted to a fully end-to-end process later on, prior to phase III clinical trials.

Hybrid manufacturing may be favored over end-to-end methods because they require less automation and can be established more rapidly. However, semi-continuous manufacturing workflows are less efficient than end-to-end setups and do not deliver the full productivity benefits of a fully continuous process.

End-to-end manufacturing, on the other hand, uses a fully integrated continuous workflow covering all steps from cell culture to final product purification. This means that there is a constant flow of materials across the entire production chain to maximize efficiency. Fully end-to-end continuous manufacturing platforms help to ensure the highest yields, smallest manufacturing footprint and highest quality while avoiding the risk of scaling up processes and lowering the cost of goods (COGs).

These numerous strengths mean that end-to-end continuous manufacturing is swiftly gaining traction amongst leading biopharma companies seeking a lower cost production method and a competitive advantage.

Boosting productivity with intensified processes

Intensified cell perfusion cultivation is an advanced bioprocessing technique designed to enhance cell growth and product yield in biomanufacturing. It allows for continuous feeding of fresh media while simultaneously removing spent media, resulting in high cell densities, consistent viability and enhanced product quality in continuous manufacturing workflows. Advanced process controls and analytical technologies used in intensified cell perfusion cultivation help to maintain consistent conditions within the bioreactor.

Experts in perfusion processes are capable of directly scaling up these cultures from 3- to 500- or 1,000-liter bioreactors suitable for both clinical and commercial applications. This enables a seamless transition from process development through to late-stage manufacturing and commercial supply.

Combining this intensified continuous process with a highly productive cell expression system can enable exceptionally high titers of biotherapeutic material, often exceeding 4 g/l/day, and provides manufacturers with additional opportunities to refine the different quality attributes of their candidate.

Improved host productivity and throughput also help to reduce the facility footprint required to generate the same volume of end product, enabling production to take place in modular clean rooms that can be rapidly installed into existing facilities or constructed separately using parallel construction techniques.

The smaller facility footprint further lowers the overall cost of therapeutic protein manufacture, making it possible to achieve a COGs of below $50/g in some instances – 75% less than the current industry standard.

Summary

Biopharmaceutical manufacturers can dramatically improve their product yields and quality by switching from a batch, fed-batch or hybrid manufacturing process to a fully end-to-end continuous workflow. These efficiency gains can be multiplied by adopting an intensified perfusion cell culture process and highly productive cell expression system.

Overall, end-to-end continuous manufacturing has the potential to lower manufacturing costs, providing the opportunity to reduce the price tag of biologics and biosimilars to ensure broader access to these essential therapies.