The Biologics Bottleneck: How Conventional Manufacturing Technologies Limit Access

Over the past two decades, biotherapeutics, particularly monoclonal antibodies (mAbs), have transformed the therapeutic landscape for a range of prevalent health conditions, from autoimmune diseases to cancers. It’s also been estimated that some 7,000 rare disease indications could be addressed with biotherapeutics ⁽¹⁾. However, while biologics have shown remarkable efficacy in clinical settings, access to these therapies remains a significant challenge globally.

Most biologics developers rely on fed-batch systems for bioproduction. However, this approach brings several key challenges that create risks and inefficiencies in the production pipeline, including:

• High manufacturing costs
• Difficulty in adapting to demand
• Expensive and risk-prone commercial development process

In this blog, we’ll explore these major factors influencing the supply and access of commercial biologics, before highlighting how adopting a continuous manufacturing approach can address these challenges.

Challenges in biotherapeutics supply and access

High manufacturing costs

Fed-batch manufacturing involves discrete unit operations where production occurs in separate, sequential steps. Each step must be completed before the next one begins. This means large volumes of intermediates must be stored, which requires a substantial facility footprint.

Running these large-scale facilities is expensive and contributes to the high costs of manufacturing. Additionally, fed-batch processes often require significant manual input, needing large teams of operators for their execution, increasing costs further. As a result, fed-batch facilities run at a higher operational cost compared with continuous bioprocessing units.

Difficulty in adapting to demand

It’s challenging for biologics developers to accurately predict the take-up and global demand for a biologic, especially during early production phases. If demand is too low, it can lead to sponsors paying out for idle manufacturing capacity. Should demand be higher than forecasted, sponsors run the risk of underproduction, causing shortages and patients going without medicines.

Further adding to this problem, fed-batch processes rely on large-scale stainless-steel units for commercial supply that are expensive and time-consuming to build. This creates inflexibility, bringing difficulties in adapting fed-batch units to fluctuating demands. This scenario was experienced by the developers of rheumatoid arthritis therapy Enbrel^®. During times of increased demand, such as when new indications were approved or patient populations grew, inability to rapidly scale up production of their fed-batch process caused serious supply constraints ⁽²⁾. 

Expensive and risk-prone commercial development process

Fed-batch biomanufacturing processes face significant risk when it comes to scaling up production, especially for sponsors moving from clinical trials to commercialization. This can limit the ability of manufacturers to meet global demand.

Fed-batch processes must be scaled up by a factor of 5 to 20-fold in order to meet commercial demand, because of the inefficiency of the process.

Scaling up in this way creates the following risks:

• The large-scale process might not replicate the smaller-scale process performance
• Product quality attributes (PQAs) might change at increased scale
• A limited number of large-scale facilities exist worldwide, causing major supply issues during increased production demands

A better approach to biologics manufacturing

Biologics provide life-saving treatments, but access and supply have been limited due to their high cost structure, inflexible production processes, and unpredictable demand. Continuous manufacturing addresses these challenges by offering a more agile, cost-effective, and stable production process.

This approach involves raw materials being continuously fed into the bioprocessing system, while products are continuously yielded. By automating workflows and maintaining a steady state of operation, companies can improve scalability, adaptability, productivity, and consistency. Companies that have started their clinical journey with a fed-batch process should consider converting to a continuous manufacturing platform before commercialization to take advantage of these benefits.

Learn how continuous manufacturing can slash biologics production costs by 75 %

To maximize manufacturing outcomes, opt for an industry-leading partner like Just – Evotec Biologics. Partners can benefit from cutting-edge continuous manufacturing technologies, well-established process development systems, and state of the art J.POD facilities.

Learn more about Just – Evotec Biologics’ continuous manufacturing solutions and how they can benefit your biomanufacturing needs

 

References

1. Chediak L. I have a rare disease. This is my hope for the future of medicine. World Economic Forum.

2. Gellene D. Immunex says Enbrel shortage worse than anticipated. Los Angeles Times. 

Very Large-Scale (VLS) production facilities have traditionally been used for the commercial supply of biopharmaceuticals. Some commentators  argue that there is no need to break with this orthodoxy. Yet many sponsor companies and CDMOs are making a concerted effort to establish continuous drug substance manufacturing. In this blog article we examine six reasons that might explain this phenomenon.

 

Why are so many innovator companies and contract manufacturing organizations making a concerted effort to establish continuous drug substance bioprocesses? 

Historically the biopharmaceutical industry has relied on Very Large-Scale (VLS) production facilities for commercial supply. Yet there are increasingly frequent calls for innovation in antibody manufacturing¹ backed by industry consortia like NIIMBL² and the BioPhorum Operations Group³. Let’s explore some of the reasons why:

 

1. Productivity: Continuous manufacturing allows significantly higher productivity than fed-batch manufacturing in VLS facilities. The current state of the art for cell line development in fed-batch processes is 8+ g/L compared with equivalent titers of 30+ g/L in perfusion bioreactors⁴. This allows antibody production in smaller, more efficient and agile facilities that deliver extremely low Cost of Goods Manufactured (COGM) while avoiding upfront scale-up costs and risk⁴.

 

2. Production Capacity: Continuous manufacturing facilities, such as Just - Evotec Biologics J.POD^® facilities, can deliver 2,000+ kg of drug substance each year and are ideal for many biotherapeutics including monoclonals, bispecific antibodies and Fc-fusion proteins. VLS facilities are designed to accommodate a small number of high-volume products.

 

3. Agility: Demand for biologics fluctuate throughout their lifecycle and is notoriously difficult to predict. This is especially true during both the product introduction phase and at the end of the lifecycle as sales are eroded by competing products. 

Commercial demand for Enbrel^®, for example, was so great when it was launched that patients’ access was restricted until the supply chain recovered⁶. In contrast, Biogen started investing $2 billion in VLS manufacturing at Solothurn, Switzerland in 2015⁷ to manufacture Aduhelm^®. The product was initially approved in June 2021 only for the company to announce it would halt sales due to a realignment of its Alzheimer’s disease franchise in January 2024⁸ leaving the company to find a new use for their facility.

Continuous biomanufacturing facilities comprising of intensified single-use platforms with production-on-demand cleanrooms are extremely agile and can be built in under two years thanks to parallel construction techniques and reduced need for WFI, SIP and CIP utilities. This contrasts with stainless steel VLS facilities which take over 4 years to bring online⁹. They require significant amounts of capital engineering leading to high depreciation costs that must be ultimately borne by the facility occupants.

 

4. Supply Chain Security with Distributed Manufacturing: Global drug shortages have put the spotlight on supply chain security in the pharmaceutical industry. These have become vulnerable for several reasons including an over-reliance on small numbers of centralized facilities in a limited number of geographical regions¹⁰.

Global networks of distributed manufacturing facilities mitigate these risks and ensure the needs of local patient populations are met despite a range of scenarios that can evolve during epidemics and pandemics. This avoids an excessive reliance on non-governmental organizations corralling manufacturers to produce specific medicines or demanding elusive new business model solutions that may or may not expand access. With the aim of increasing medicine supply chain security for their population, policymakers such as the French government have chosen to invest in industrial sovereignty in the healthcare sector. The need for this was emphasised by the health crisis caused by the COVID-19 pandemic¹¹.

 

5. Process Portability: VLS production processes suffer from having low process portability. Transferring between these facilities is neither fast, inexpensive or assured of success. The cost of transferring processes into a new VLS facility runs into tens of millions of dollars. Consider the bill for new consumables alone or the cost of packing chromatography columns with diameters exceeding 1.4 m with Protein A resins. Very few VLS facilities are identical despite what commentators would like us to believe.

In practice, these fixed pipe facilities must be re-engineered for each new unique product that is transferred into the asset. The sponsor must pay these CAPEX costs but also the cost of pilot and engineering runs required to mitigate scale-up risks. 

Just – Evotec Biologics provide true process portability by offering partners access to its technology platform under a licensing agreement so that sponsor companies can bring their products and processes in-house and fully under their control.

 

6. Sustainability: Pharmaceutical and large biotechnology companies are increasingly cognizant of their environmental impact and are setting ambitious sustainability goals. Intensifying antibody production through adopting continuous manufacturing will allow these firms to manufacture their antibody products with fewer of the earth’s resources¹². In contrast, VLS facilities require large amounts of carbon-intensive concrete during their construction phase. During operations they need significant amounts of energy to generate super-heated steam for SIP systems and highly purified water-for-injection needed for flushing cleaning solutions from stainless steel tanks.

 

References

1. Kelley, B. (2024). The history and potential future of monoclonal antibody therapeutics development and manufacturing in four eras. mAbs, 16(1). https://doi.org/10.1080/19420862.2024.2373330
2. Process Intensification Program - NIIMBL
3. BioPhorum Technology Roadmapping roadmap vision 2.0
4. J.CHO High Expression System for Continuous Manufacturing with Extraordinary Titers - Science Pool (evotec.com)
5. Garcia, F.A. & Gefroh, E. (2023) Reducing biopharmaceutical manufacturing costs through continuous processing in a flexible J.POD® facility. Drug Discovery Today, 28 (7). https://doi.org/10.1016/j.drudis.2023.103619.
6. Gellene D. Immunex says enbrel shortage worse than anticipated [Internet]. Los Angeles Times; 2002. https://www.latimes.com/ archives/la-xpm-2002-may-24-fi-immunex24-story.html
7. Biogen, awaiting FDA nod for $2B Swiss plant, plans to ship initial Aduhelm doses from North Carolina factory | Fierce Pharma
8. Biogen: how is the biotech pivoting from a failed Alzheimer's drug? (labiotech.eu)
9. FUJIFILM DIOSYNTH BIOTECHNOLOGIES BREAKS GROUND ON THE LARGEST CELL CULTURE BIOPHARMACEUTICAL CDMO FACILITY IN NORTH AMERICA | Fujifilm [United States]
10. Four ways pharma companies can make their supply chains more resilient | McKinsey
11 Evotec accelerates access to biologic therapeutics with initiation of manufacturing facility in Toulouse - Evotec Website (English)
12. Continuous Biomanufacturing Reduces Environmental Impact - Science Pool (evotec.com)

 

Learn More

Just- Evotec Biologics is pioneering a new era in biomanufacturing. Transitioning to our intensified continuous production before manufacturing at commercial scale can drive value creation in a late-stage manufacturing process. Additionally, as we offer a short feasibility study, this is a low-risk method for evaluating the benefits our workflow can bring, without impeding development timelines.

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With high attrition rates of mAbs in early phase clinical trials, it is becoming increasingly challenging for biopharmaceutical companies to rapidly deliver high quality therapeutic mAbs using conventional antibody screening and fed-batch bioprocessing methods. This is why new Quality by Design (QbD) approaches such as using in silico AI and ML platforms to discover and optimize mAb sequences, high-throughput screening, and continuous intensified manufacturing processes such as those used at Just- Evotec Biologics are critical for enabling a paradigm shift in reducing attrition rates.

As detailed in this article, optimizing mAb design, using automated, miniaturized screening, and minimizing time in culture can deliver high-quality mAbs for FIH trials in rapid response times of around 12 months. In the future using this approach could expand access to life changing treatments, as well as support a rapid response to global health emergencies.

 

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Download our presentation from Recovery of Biological Products XX titled “Turning the crank using a hybrid continuous purification platform” from Michelle Najera, Megan McClure, Shahbaz Gardezi and Beth Larimore. 

Learn how:

1. Process intensification solutions for monoclonal antibodies, Fc-fusion proteins and bispecific antibodies t ease liquid handling pain points.
2. Our J.CHO^TM High Expression System is delivering perfusion permeate titers of over 2 g/L/d over 25 days.
3. Continuous capture chromatography significantly enhances resin utilization
4. Two tank virus inactivation steps can be developed with bench-scale models

Download the Presentation

 

By leveraging intensification, minimization, and simplification in bioprocessing workflows, Just-Evotec Biologics can achieve higher productivity, better resource utilization and lower facility costs. Collectively, these benefits contribute to reducing the COGM of biotherapeutics.

Download our whitepaper

 

This poster describes the rapid conversion of an intensified fed-batch antibody manufacturing process to an integrated continuous biomanufacturing process using the Just-Evotec Biologics platform, resulting in several key project accomplishments: 

• Mitigation of upstream IFB challenges
• Significant productivity increase
• Short development time
• Minimal risk from changes in product quality

These results demonstrate that the rapid conversion of fed-batch processes for monoclonal antibodies to an integrated continuous biomanufacturing process can be achieved with a robust ICB platform. This supports the biotherapeutics industry’s need to quickly adapt to changing clinical and business circumstances.

Download our poster

Biologics manufacturing typically uses engineered Chinese Hamster Ovary (CHO) cells to produce folded and glycosylated antibodies. Determining the optimum conditions to grow and maintain cell culture often requires considerable time and effort.

A quantitative understanding of cell metabolism through an analysis of cell culture metabolites can enable optimization growth conditions for improved titles or increased perfusion duration. Mass spectrometry is the optimum tool for metabolite measurement, however, transforming raw data into accurate quantitative measurement requires both expertise and extensive sample preparation.

In this poster we demonstrate the ability of simple sample preparation using universal calibrators and a novel machine learning algorithm to rapidly provide biological insight into bioprocessing samples taken from perfusion cell cultures.

Download our poster