Biotech manufacturing, especially the development of biologics like monoclonal antibodies, has become a highly complex and evolving field. As the demand for therapeutic proteins continues to rise, scientists and engineers face numerous challenges in optimizing production processes while managing costs.
This article explores some of the key issues and trends in bioprocess development, offering insights from seasoned experts in the industry. This concept is discussed in greater detail in an episode of the Smart Biotech Scientist Podcast, with Brian Kelley and hosted by David Brühlmann, founder of Brühlmann Consulting.
Key Challenges in Bioprocess Development
Technical Challenges in Biologics Manufacturing
Biotech companies are constantly working to improve the efficiency and cost-effectiveness of their manufacturing processes. However, one of the primary technical challenges remains the unpredictable behavior of living cells used in production.
Whether using mammalian cells (e.g., CHO cells) for monoclonal antibody production or yeast and microbial cells for other biologics, every cell line exhibits unique characteristics that can significantly affect yield, quality, and overall process performance.
In particular, mammalian cell culture, commonly employed for monoclonal antibody production, remains difficult to optimize due to the incomplete understanding of cell metabolism and behavior.
Despite advances in research, experts acknowledge that a full grasp of how these cells function—particularly their complex metabolic pathways—may never be fully realized. This variability, often referred to as the "personality" of the cell line, can present significant challenges in ensuring consistency and reproducibility in production.
Cultural and Organizational Barriers
In addition to technical hurdles, there are cultural and organizational challenges in bioprocess development. Within biotech companies, a disconnect sometimes exists between the research and clinical development teams and those focused on technical operations, including process development and manufacturing. As these companies push forward with new therapeutic discoveries, process engineers and biotechnologists can struggle to convey the importance of their work to non-technical stakeholders, such as senior management or finance departments.
For example, executives and finance teams may not fully appreciate the complexity and cost associated with bioprocess development, particularly in the early stages of clinical trials. This misalignment can lead to difficulties in justifying investments in process optimization, even though the success of clinical trials often hinges on the robustness and scalability of the manufacturing process.
The Rising Costs of Biologics Manufacturing
Factors Affecting the Cost of Antibody Production
The cost of manufacturing monoclonal antibodies and other biologics is influenced by various factors, with raw material expenses being one of the most significant contributors. Key inputs such as culture media, cell culture supplements, and chromatography resins can drive up costs substantially.
For instance, proprietary media used in Chinese Hamster Ovary (CHO) cell culture can be one of the largest cost drivers in recombinant protein production. The sheer scale at which these materials are procured—ranging from large global companies to smaller biotech firms—can create significant price disparities.
One of the highest costs in the downstream purification process comes from the use of Protein A resins, which are required for capturing monoclonal antibodies. Although reusable, these resins are costly, particularly in the early clinical stages. Despite efforts to develop alternatives, Protein A remains the standard, and its price continues to affect the overall cost of goods (COGs).
Another hidden cost is the use of virus removal filters during purification. These filters are single-use only, meaning that their cost per gram of purified antibody can become a significant factor in overall production costs.
Contract Manufacturing and Time-to-Market Costs
For companies that outsource manufacturing to contract development and manufacturing organizations (CDMOs), there are additional cost factors to consider. The time it takes to complete a batch of monoclonal antibodies can directly impact the cost per batch. The longer the manufacturing cycle, the higher the labor and overhead costs.
Furthermore, CDMOs may have to prioritize between multiple clients, meaning that the cost efficiency of a manufacturing partnership can vary significantly depending on the availability of resources and facility capacity.
However, the real cost savings often come from reducing the manufacturing cycle time. The faster a contract manufacturer can produce a batch, the lower the cost per unit, which is why some companies are investing in technologies that accelerate production without sacrificing product quality.
Balancing Quality and Cost In Bioprocess Development
Striving for Speed and Cost-Effectiveness
Biotech companies often face the delicate balancing act of ensuring high-quality output while maintaining cost-effectiveness. For smaller companies, particularly those in early clinical development, minimizing costs while ensuring robust manufacturing processes can be challenging. Speed-to-market is critical in the pharmaceutical industry, as a delay in clinical trials can lead to significant financial losses and a competitive disadvantage.
To navigate this tension, it's crucial to establish clear priorities at the outset of a project. Ensuring product quality, for instance, should always be the top priority. This includes maintaining compliance with regulatory standards and executing successful, reproducible manufacturing runs.
High-quality manufacturing, particularly in the early stages, can also help mitigate downstream risks, such as failed clinical trials due to subpar product quality or regulatory issues.
I'd like to go fast. I'd like to have a high probability of technical success with the CDMO, for instance. But I also want that very high quality insurance of no regulatory risk associated with that manufacturing and production. I guess I'm asking for it all.
Collaboration with CDMOs
Working with contract manufacturers (CMOs) or contract development and manufacturing organizations (CDMOs) requires careful selection based on the company's ability to deliver high-quality results. In the case of monoclonal antibody production, choosing a CDMO that can scale from early-phase to late-phase manufacturing without compromising on quality is essential.
To ensure success, biotech companies must maintain a collaborative partnership with CDMOs, fostering open communication about expectations and timelines. Quality control and compliance are vital, as failing to meet regulatory standards could derail a project.
Continuous monitoring of the CDMO’s performance—especially in terms of documentation, compliance, and successful regulatory inspections—is key to managing the risks associated with outsourcing manufacturing.
While a CMO can provide the necessary technical expertise and infrastructure, it is important to remember that "you get what you pay for." Therefore, a well-established reputation and a track record of successful manufacturing runs are valuable when selecting a partner for biologics production.
Practical Strategies for Reducing Manufacturing Costs in Antibody Development
As the biopharmaceutical industry continues to advance, the pressure to reduce manufacturing costs while maintaining high-quality standards has never been more critical. For companies aiming to bring the next blockbuster antibody therapy to market, optimizing the development and manufacturing process is essential.
The Importance of Economies of Scale in Antibody Manufacturing
When it comes to reducing manufacturing costs, one of the most effective strategies is to capitalize on economies of scale. In the context of antibody production, larger batch sizes play a significant role in driving down the cost per dose. This is particularly true in the production of antibodies intended for global distribution, such as those aimed at treating infectious diseases in the developing world.
Larger batches allow for cost efficiencies in testing and stability, as these costs scale with the number of batches produced. By focusing on scaling up production volumes, companies can dilute these fixed costs over a larger quantity of product, significantly lowering the overall cost per gram and, ultimately, the cost per dose.
Maximizing Titers for Cost Efficiency
Another crucial driver of cost reduction in antibody manufacturing is optimizing productivity during the cell culture stage. Higher titers—measuring the concentration of antibodies produced per liter of culture media—can substantially lower the number of batches needed for large-scale production. A 60-70% increase in titers from, for example, 5 grams per liter to 8 or 9 grams per liter, can significantly reduce both the number of batches and cost of goods.
For companies developing antibodies for less demanding markets, such as those targeting infectious diseases, the focus should be on maximizing titers during the development stage, particularly in Phase 3 development, to ensure that production costs are minimized as the therapy advances toward commercialization.
I'd love to have people believe that the simplicity of the established antibody manufacturing platform, its portability for companies, innovator companies to be able to take a manufacturing process from their clinical facility to a large CDMO. Maybe multiple dual source manufacturing is a huge advantage. So when we can keep it simple, I think we should.
Overcoming Challenges in Small-Scale Production
In cases where large-scale production is not feasible—either due to lower demand for the product or other constraints—cost reduction efforts must shift focus. For products with small-volume demand, such as those with highly potent formulations that require only small doses, the cost of goods is less significant than in blockbuster drugs. In these cases, trying to reduce manufacturing costs drastically may not yield substantial savings.
However, companies may still find value in pursuing innovation, especially when it comes to manufacturing processes and raw materials. Introducing novel approaches in production may carry risks but could also provide long-term benefits if the processes prove scalable and robust enough for commercial production.
Innovation in Antibody Manufacturing: A Marginal Approach
While innovation remains a driving force in many areas of biotech, it's important to recognize that in the well-established field of monoclonal antibody manufacturing, major breakthroughs are unlikely to reduce costs drastically. The technology has matured over the past four decades, with established processes, well-understood bioreactor management, and well-documented cell line development strategies.
For companies operating within the mAb space, incremental improvements are more likely to yield results than revolutionary changes. Innovations such as improving expression vectors or developing optimized media could help push titers higher and make production more efficient, but in general, these innovations will only lead to marginal gains in the cost-reduction strategy.
The Focus on New Modalities: Cell and Gene Therapy
Looking ahead, the potential for significant innovation lies in new therapeutic modalities, particularly cell and gene therapies. Unlike monoclonal antibodies, these therapies often involve more complex production processes that present new challenges in terms of manufacturing scalability, consistency, and cost control.
For example, gene therapies that utilize adeno-associated viruses (AAVs) as vectors could benefit from platform manufacturing models. This would enable greater standardization and efficiency, similar to the successful platform manufacturing model established in monoclonal antibody production. By leveraging existing knowledge in biologics manufacturing, companies could lower costs, streamline production, and make these therapies more accessible.
A New Era for Monoclonal Antibodies?
The antibody therapeutics landscape is entering an exciting new phase of development. Advances in high-titer production combined with the construction of large-scale contract development and manufacturing organizations (CDMOs) have created a more competitive manufacturing landscape. These developments have the potential to lower the cost of goods dramatically and, subsequently, the price per dose for monoclonal antibodies.
Moreover, establishing large CDMO facilities in strategic locations like Denmark, South Korea, North Carolina, and Switzerland creates unprecedented manufacturing capacity. This expansion, combined with advances in high-titer production, enables production at scales previously unattainable.
What makes this particularly promising is the potential impact on therapeutic accessibility. The combination of large-scale facilities and improved titers leads to larger batches, which in turn results in lower cost of goods and ultimately reduced price per dose. This development opens new horizons for antibody therapeutics in previously challenging areas.
The industry is also expanding into new therapeutic territories. Recent developments include antibodies being developed for:
- Treatment of high cholesterol
- Prevention of migraine headaches
- Treatment of Alzheimer's disease
These therapeutic areas might not have been considered viable targets for antibody therapy two decades ago, demonstrating the field's continued evolution.
For global health challenges, particularly in developing nations, this manufacturing evolution could be transformative. The ability to leverage these large manufacturing facilities through funding from global health organizations or foundations could make biosimilar antibodies more accessible. This could potentially expand treatment options for infectious diseases, oncology, and inflammatory conditions in low and middle-income countries.
However, the path forward isn't just about manufacturing capacity—it's about making these therapies truly accessible to those who need them most, a challenge that remains at the forefront of the industry's concerns.
Biosimilars: The Next Frontier in Cost Reduction
One significant development is the rise of biosimilars. These therapies, which are highly similar to approved branded monoclonal antibodies, offer the potential to reduce costs through competition. As biosimilar markets expand, prices for many monoclonal antibodies are expected to decrease, making these therapies more accessible to a larger global population.
Moreover, biosimilars could play a critical role in addressing global healthcare needs, particularly in low- and middle-income countries. By decreasing the overall cost of antibody production and enabling the use of established manufacturing processes, these therapies could be distributed more widely, improving global access to life-saving treatments.
Leveraging Lessons From Monoclonal Antibodies for Gene and Cell Therapies
Interestingly, some of the manufacturing efficiencies seen in monoclonal antibody production could translate to newer therapeutic areas, such as cell and gene therapies. The concept of platform manufacturing, where standardization and modular processes are emphasized, could be applied to gene therapies in the future.
For instance, companies developing cell and gene therapies could adopt some of the same principles used in monoclonal antibody production—focusing on optimizing production processes, improving raw material sourcing, and leveraging platform technologies. While cell therapy is currently more complex due to the individualized nature of treatments, platform approaches could help improve scalability and reduce costs over time.
The Future of Antibody Manufacturing: A Growing Market
Looking ahead to the next 5-10 years, the demand for biotherapeutics is expected to grow significantly. As biosimilars continue to proliferate and newer, more targeted antibody therapies emerge, competition will drive innovation and efficiency in manufacturing processes.
At the same time, the development of bi-specific antibodies—which combine the properties of two distinct antibodies in a single molecule—could drive further growth in the biologics market. Although developing platforms for these novel formats presents unique challenges, they offer exciting possibilities for the future of immunotherapy.
Conclusion
In conclusion, while the drive for innovation in biopharmaceutical manufacturing remains strong, it’s important to recognize that in the mature field of monoclonal antibody development, incremental improvements rather than radical changes are more likely to drive cost reductions. Focus on scaling up production, optimizing titers, and using established platforms to reduce costs in large-scale antibody manufacturing. At the same time, look to emerging therapies like cell and gene therapies for the next frontiers of innovation and cost-effective manufacturing.
As the industry evolves, one thing remains clear: simplicity is key. By optimizing existing processes and leveraging established technologies, companies can navigate the complexities of the biopharmaceutical space, ensuring that therapies are both effective and accessible to those who need them most.
About Brian Kelley
Brian Kelley is the Senior Vice President of Process Development at VIR Biotechnology. Formerly, Brian was Vice President of Bioprocess Development at Genentech, covering bioprocess development, validation, and technology transfer. Prior to this, he worked 15 years at Genetics Institute/Wyeth in Andover, MA. He was an adjunct faculty member at Tufts University for 15 years where he taught graduate classes in biotechnology.
He obtained his B.S. in Chemical Engineering from the University of Wisconsin-Madison, and his Ph.D. from MIT. Brian is a member of the National Academy of Engineering, has chaired the Recovery of Biological Products Board, and has been recognized by the American Chemical Society’s Biotechnology division with the Michaels Award for contributions to the field of bioseparations.
Connect with Brian Kelley on LinkedIn.
David Brühlmann is a strategic advisor who helps C-level biotech leaders reduce development and manufacturing costs to make life-saving therapies accessible to more patients worldwide.
He is also a biotech technology innovation coach, technology transfer leader, and host of the Smart Biotech Scientist podcast—the go-to podcast for biotech scientists who want to master biopharma CMC development and biomanufacturing.
Hear It From The Horse’s Mouth
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