Russell Miller, VP, global sales and marketing, Enzene shares how to drive down the cost of monoclonal antibody manufacturing.
Enzene
Monoclonal antibodies (mAbs) have become central to modern biopharmaceutical therapy, with clinical applications spanning oncology, autoimmune diseases, and infectious disorders. Yet despite their clinical significance, mAbs remain expensive to manufacture, posing a persistent barrier to affordability and access, particularly in resource-limited settings.
With biotech companies still struggling to secure funding and capital markets remaining tight, there is a growing imperative to stretch resources and reduce the cost of this promising modality. Rising manufacturing costs, compounded by economic uncertainty and pricing pressures, make cost optimisation a strategic priority across the sector.
The traditional approach to mAb manufacturing relies on large-scale fed-batch processes, which are costly, complex, and difficult to adapt. Production costs often range from $150 to $300 per gram, driven by both the complexity of the molecules and the inefficiencies of legacy systems. These challenges have prompted growing interest in new methods that can reduce costs while maintaining quality.
This article outlines the limitations of conventional manufacturing approaches and examines how process innovations particularly Fully-Connected Continuous Manufacturing (FCCM) are being leveraged to address them. It highlights strategies being employed to lower costs, and efforts aimed at achieving an industry-low figure of $40 per gram for mAbs.
The challenge of manufacturing complexity
Manufacturing mAbs is inherently more challenging than producing small molecules. It involves cell-line development, upstream culture, multiple purification steps, virus inactivation, and rigorous quality control—each stage introducing cost, time, and regulatory burden.
Traditional fed-batch processes dominate the industry. These are typically run in large stainless-steel bioreactors, with each production step followed by a hold and transfer phase. While robust and well understood, fed-batch operations demand high capital investment in utilities, large columns, cleanroom infrastructure, and storage capacity. Moreover, hold steps between unit operations introduce risks related to contamination, protein degradation, and time delays.
Continuous manufacturing is gaining traction, as it supports ESG goals and offers benefits such as lower costs, shorter timelines, and greater process flexibility. However, its industry-wide adoption has been slow largely due to legacy infrastructure in large pharmaceutical companies. Many of these firms have invested heavily in fed-batch systems making the transition to continuous operations both costly and operationally disruptive.
That said, the landscape is rapidly evolving. A growing number of companies, specially several smaller or newer players without such legacy constraints are demonstrating that continuous approaches can be commercially viable. For instance, some have successfully manufactured mAbs using integrated platforms with perfusion-based upstream and multi-column downstream units.
Still, misconceptions about continuous manufacturing persist across the industry. A common issue is the misclassification of batch processes that incorporate one or two continuous steps as full CM systems, which can create unrealistic expectations around yields and consistency. Another widely held belief is that CM only becomes cost-effective at very high production volumes. This is not true as technological advances have shown that CM can deliver both flexibility and economic value at smaller scales.
A step further in continuous bioprocessing is the Fully Connected Continuous Manufacturing platform, which integrates upstream perfusion culture with continuous downstream purification and virus inactivation in a compact, uninterrupted system. This approach has already been deployed at commercial scale by Enzene for monoclonal antibody production using its patented EnzeneX platform. By enabling seamless operation without intermediate hold steps, the platform has demonstrated a tenfold increase in upstream productivity compared to conventional fed-batch methods, along with an estimated 50% -80% reduction in production costs.
The platform achieved titres of 120 g from a 2-litre bioreactor for a Nivolumab biosimilar, breaking the 50 g/L barrier and brought down the cost of manufacture to $80-$100/g. EnzeneX 2.0, the next generation of this system, is being scaled to produce 40 kg from a 1,000-litre bioreactor. The company forecasts a production cost of $40 per gram for select stable clones-well below current industry averages.
Strategies for further reducing cost per gram through FCCM optimisation
Achieving a lower cost of biologics manufacturing such as Enzene’s $40-per-gram target requires optimisation across multiple stages of the production process. Key areas of focus include upstream intensification, streamlined downstream integration, smarter use of process analytical technologies (PAT), and more efficient raw material strategies.
1. High-density perfusion cultures
One of the most impactful strategies involves upstream intensification. Perfusion systems which allow for the continuous feeding of fresh media and removal of waste are enabling cell densities of 80–120 million cells/mL over a prolonged period. Higher cell density directly improves yield and reduces the number of batches needed to meet supply targets, thereby lowering cost per gram. Importantly, this also reduces the number of bioreactor runs required, with direct implications for cost, facility utilisation, and throughput.
2. Media optimisation
Another critical area of innovation is media formulation. Because perfusion cultures operate over extended periods, often 25 to 35 days, the volume and cost of media become significant. To address this, some manufacturers are adopting ‘lean media’ strategies. These involve analysing spent media to identify underutilised components and adjusting concentrations accordingly. Reducing unnecessary nutrients without compromising cell health or productivity lowers media costs and reduces environmental impact.
3. Multi-column chromatography
Downstream, continuous chromatography systems using multiple smaller columns in tandem can significantly improve purification efficiency. These systems enable near-continuous purification without the need for large resin volumes or hold tanks. Designed to optimise resin usage over a single production cycle, they reduce resin and buffer consumption and minimise equipment footprint. In some platforms, resin is discarded after a single high-frequency-use cycle, eliminating the need for storage and cleaning validation protocols.
4. Real-time release and PAT
Embedding Process Analytical Technology (PAT) enables real-time monitoring of critical process parameters and product attributes. With real-time release testing (RTRT), batches can be released immediately after production, reducing quality control bottlenecks and storage needs. This level of integration is foundational to the future of continuous biologics manufacturing.
In parallel, discussions are ongoing around incorporating RTRT into the FCCM framework in alignment with USFDA guidelines. This shift would represent a significant advancement toward leaner, faster, and more responsive manufacturing models.
Overall, reducing the cost of monoclonal antibody manufacturing remains a key priority for improving global access to biologics. FCCM offers not just incremental improvement, but a fundamental rethinking of how biologics can be produced — efficiently, affordably, and at scale. By integrating advanced upstream intensification, leaner downstream processes, and real-time analytics, end-to-end continuous platforms are pushing the boundaries of what’s possible, driving costs down to unprecedented levels.