Science Pool

Just-Evotec Biologics’ continuous manufacturing platform is enabled by a range of innovative technological solutions. Magnus Schroeder, VP Process & Product Design described the technology advances that we have applied to allow fully continuous downstream processing at BPI West San Diego. 


These include:

•    Key enables of continuous process technology
•    Custom skid designs for continuous operations
•    Dynamic modelling approach for CM
•    Continuous viral filtration

For a more detailed discussion contact us at: info@evotec.com

Download Some of the Highlights of his Presentation Here

Just - Evotec Biologics is constructing a new biomanufacturing facility in Toulouse, France. The facility applies the company’s successful J.POD design featuring a single-use continuous cell culture manufacturing platform set inside production-on-demand modules within a ballroom manufacturing space. The investment of approximately €150 million was announced in April 2021 and the company broke ground on the project in September 2022. In October last year the building shell was completed and the autonomous cleanroom POD installation occurred at the beginning of this year. Now the equipment will be installed into the cleanroom PODs ready for the facility to be operational in the second half of 2024.

At the core of this endeavour lies the innovative J.POD biomanufacturing facility developed by Just – Evotec Biologics. J.POD facilities contain the company’s continuous manufacturing platform for antibodies and other therapeutic proteins with an Fc-region. The continuous process is so highly intensified that it can be contained within production-on-demand modules that sit within a ballroom cleanroom space. The design is central to the company’s mission: to design and apply groundbreaking technologies that dramatically expand global access to biotherapeutics.

The J.POD design is commercial biologic manufacturing-ready but can also easily deliver batches for clinical trials. The ability to modulate capacity easily depending on the lifecycle stage of the molecules is one of the advantages of continuous manufacturing.

Transitioning to Continuous Manufacturing

Traditional fed-batch manufacturing methods have long been the standard for producing biologics. However, switching to continuous manufacturing with a high degree of intensification reduces the cost of goods manufactured (COGM) of biologics to less than $50 per gram by reducing the cost of building and running biomanufacturing facilities.

The use of pod modules in the design of J.POD Toulouse allow for greater agility, readily expandable facilities, and lower risk. Unlike traditional methods that require scaling up to larger production trains, the J.POD approach ensures flexibility in meeting demand fluctuations. This is extremely valuable to companies that launch new products and find it difficult to predict the ramp up in market demand.

By expanding into Europe, J.POD Toulouse enhances the company’s ability to support customers based in Europe, effectively. With facilities on both sides of the Atlantic, the company is providing supply chain security by having duplicated capacity in two geopolitically stable regions.

Just - Evotec Biologics' announcement last year of a multi-year, long-term tech partnership with Sandoz to develop and manufacture multiple biosimilars in J.POD facilities demonstrate the industry’s readiness to embrace continuous production methods.

Process Development Capabilities

To support manufacturing operations J.POD Toulouse facility houses robust process development capabilities, including:

1. Cell Line Development: Streamlining the creation of high-yield cell lines for antibody production.
2. Upstream & Downstream Process Development: Optimizing the entire continuous production process, from cell culture to purification.
3. Formulation Development: Crafting stable and effective formulations for therapeutic molecules.

Conclusion

J.POD Toulouse prepares to open its doors with its commitment to cost-effectiveness, scalability, and supply chain security. This facility stands poised to transform the way we produce lifesaving biotherapeutics. Watch this space—J.POD Toulouse is about to make waves in Europe and beyond.

This project benefits from French government funding as part of the Investments for the future Programme (programme d’investissements d’avenir in French) and is also supported economically by the Occitanie Region.

Patients around the world need access to affordable biopharmaceuticals to treat life-threatening conditions. High manufacturing costs can make these medicines unaffordable and limit their use amongst global patient populations. Historically, the biopharma industry has manufactured these medicines in large-scale stainless steel production facilities. Such facilities take years to construct and require over $500M of upfront capital investment. The cost of manufacturing biologics in these production plants is high and especially inefficient when asset utilization is low.

To reduce production costs, the industry increasingly recognizes that the next generation of production facilities must break with existing manufacturing paradigms. New facilities must be small and agile with intensified manufacturing platforms that allow extremely high productivity to meet late phase clinical and commercial demand.

Agile J.POD Facilities

Just-Evotec’s J.POD facilities apply modular technology to reduce the footprint of cleanrooms. Our facility design minimizes the expensive utilities needed to run a stainless-steel plant and instead leverages fully single-use and continuous biomanufacturing platforms. We culture mammalian cell hosts in perfusion bioreactors that we connected to a continuous purification train. In this way we can sustain volumetric productivities of over 2 g/L/day and continuously purify antibody during the production run making efficient use of production equipment.

The CAPEX associated with a J.POD facility is less than $200M. Our J.POD Redmond facility is operational in Washington, USA while we will bring a new European facility online in Toulouse, France in 2024. These facilities in two geopolitically stable locations will provide our customers with additional supply chain security.

Comparing J.POD to Traditional Facility Designs

Just-Evotec Biologics production engineers use models and associated visualization tools to optimize production costs. These tools show the relationships between facility design, production demand and drug substance manufacturing costs. Our engineers created mathematical models of a large-scale stainless steel and our J.POD facility. They used Net Present Cost (NPC) to compare scenarios. NPC estimates cash flows by computing operational costs and discounting over time using a capital parameter. It does not include revenues in the accounting of cash flows and assumes capital costs incurred at the beginning of the project are sunk costs.

Engineers took the following approach to compare the stainless steel and J.POD facility designs:

1. They generated 512 different patient population curves. (example is shown in the lower graph of Figure 1)
2. They estimated bioreactor capacity and utilization needed to deliver the mass of product required by these patient population curves for both facility types. (example is shown in the middle graph of Figure 1)
3. The engineers ran the model to estimate the manufacturing costs associated with each facility production mass output. (example shown in in upper graph of Figure 1).
4. The team used NPC calculation to produce a concise estimate of cash expenditures over time and normalized these values by their corresponding mass outputs. They assembled histograms to visualize the underlying statistical distributions behind a particular facility configuration (Figure 2).

Figure 1. The determination of manufacturing costs associated with two different biopharmaceutical manufacturing facilities producing sufficient drug product to meet the needs of a specific patient population curve.

Figure 1 shows that a stainless-steel facility has a higher initial cost at Year 0 because of the high capital expense allocation and has higher fixed costs than the J.POD facility over the operating period.

Figure 2 shows the benefits derived from the agility of the J.POD facility design. The NPC over the operating period was lower in the J.POD facility than the stainless-steel facility in every scenario modeled. The width of the NPC distribution for a POD-based facility is narrower than that of a stainless-steel facility. The production costs associated with a J.POD facility are largely independent of capacity utilization because of the lower upfront capital costs. Furthermore, managers have the option to expand capacity if needed by reacting to market demand estimates on a yearly basis. This is a significant advantage of the J.POD facility because managers can tailor plant capacity within the network to the latest market projections, making it more capable of reacting to disruptions or demand fluctuations.

Figure 2: Histogram depicting normalized Net Present Cost (NPC) estimates for both facility types.

Agile Efficient Biomanufacturing

J.POD facilities are inexpensive to construct and commission due to their small size and use of single-use technologies that limit the amount of plant utilities needed. We can quickly deploy these assets in response to fluctuations in demand forecasts. Production within J.POD facilities is very efficient due to the continuous manufacturing platform and the ease with which we can modulate capacity to maximize asset utilization. J.POD facilities are leading the transition away from expensive large-scale stainless steel production assets towards more agile and lower cost biopharmaceutical manufacturing. Access to these remarkable facilities is available to Just-Evotec Biologics customers through our innovative partnering arrangements. Together with our partners we are reducing the costs of biologics and making them more accessible to patients around the world.

Read the Full Article Here

A recent publication in Nature Medicine further validates Just – Evotec Biologics’ J.MD^TM Molecular Design suite. 

Children under the age of 5 years account for more than 75% of deaths attributable to malaria. The World Health Organization (WHO) has recommended the vaccine Morsquirix for paediatric use, but it has modest efficacy. Monoclonal antibodies and other complementary strategies are critically important in efforts to eradicate this disease. 
 
A multi-disciplinary team of scientists from multiple organizations collaborated on a project to select and engineer a potent and long-lasting antibody drug with anti-malaria activity. Key to this mission was to develop an antibody with developability properties amenable for cost-effective manufacturing and dosing in paediatric populations. 
 
Scientists from Just – Evotec Biologics played a crucial role in the project. They helped with the lead candidate selection by ranking a panel of human-derived potential antibody candidates for developability using Just - Evotec Biologics’ in silico Abacus tool. Abacus is a component of our J.MD^TM Molecular Design suite of tools for antibody research and development. Once the team had selected a lead and backup candidates, Just - Evotec Biologics scientists designed optimized variants of the candidate antibodies with greatly improved developability properties informed by stability violations found with the Abacus tool. 
 
Scientists used stable pools to express the optimized designs and generate material for biophysical characterization and activity assays. This enabled the final lead selection of AB000224 and AB007088 for advancement as a clinical lead and backup. The team engineered the variable domains of both antibodies to enable low-cost manufacturing at scale for distribution to paediatric populations. 
 
Just-Evotec Biologics scientists identified the best-producing clonal cell line, expressing the candidate molecule in continuous-perfusion bioreactors at twice the original titre. They advanced the candidate into production following good manufacturing practices. The material generated from this production run is being used to support studies for clinical development of an antimalaria drug suitable for use in paediatric populations living in Low to Middle Income Countries. 

Learn more in the following article published in the prestigious journal, Nature Medicine. 

Learn More

Watch our first virtual roundtable on continuous manufacturing of biologics. Together with industry thought-leaders we aim to discuss current trends in biomanufacturing in this series. For this session we invited Brian Kelley, SVP Process and Product Development at Vir Biotechnology and Randal Bass, EVP Process Design and Biotherapeutic Operations at Just-Evotec Biologics. They discuss "How real is continuous manufacturing and what are the challenges?".

Want to learn more? Reach out to us at info@evotec.com

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Watch the 20 minute interview with Jon Gunther, VP Business Development Just-Evotec Biologics, at Biomanufacturing World Summit 2023. For a complete table of content regarding Jon's discussion, please see below.

Table of Contents

0:00 min – 01:50 min
Intro + Discussion on biomanufacturing costs and making biotherapeutics more affordable and accessible to patients worldwide

01:51 min –5:06 min
Emergence of continuous manufacturing of biologics to reduce cost of goods manufacturing (COGM)

5:07 – 7:00 min
Switching from fed-batch to continuous manufacturing, quality requirements and stance of the FDA

7:01 – 08:32 min
Timelines for switching to continuous manufacturing

08:33 –10:42 min
Pharma 4.0 / Using state-of-the-art technology incl. lights-out manufacturing approach

10:43 – 13.42 min 
Highly flexible manufacturing approach with Just-Evotec Biologics’ J.POD cGMP manufacturing facilities in North America and Europe

13.43 – 16:30 min
What should commercial partners observe in terms of cost, quality, scale-up and how this process can be de-risked

16:31 – 17:30 min
J.POD’s flexible and de-risked manufacturing approach when going from late-stage clinical to commercial supply

17:31 – 19:44
Our flexible partnership model incl. options like with our tech partnership with Sandoz for biosimilars development and commercial manufacturing

19:45 – end
Closing comments, get in touch with us!

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The biopharmaceutical industry must break with existing manufacturing paradigms if it is to reduce the cost of biological medicines and ensure they are accessible to patients around the world. The industry’s next generation of production facilities will use innovative approaches to minimize clean room space utilization, reduce the footprint of facilities and lower production costs.

In order to meet the global demand for biological medicines in these small and agile productions facilities, intensified manufacturing platforms are being developed that allow very high productivity to meet late phase clinical and commercial demand. These platforms utilize mammalian cell hosts in perfusion bioreactors linked to continuous downstream trains. Cell culture productivities have reached a point where a bioreactor can sustain a volumetric productivity of more than 2 g/L/day. This, coupled with the development of low-cost media and advancement in process automation technologies around the bioreactor, has translated to an ability for companies to operate a single-use bioreactor uninterrupted for over 15 days and execute harvest and Protein A capture on a continuous basis.

Optimizing Continuous Biomanufacturing Operating Conditions

Engineers at Just-Evotec Biologics were challenged to find the optimum operating conditions to enable the lowest production costs irrespective of facility mass output. To achieve this aim, they developed process models for our continuous process contained within a J.POD® facility. 

J.POD facilities apply modular cleanroom pod technology arranged in a controlled, non-classified ballroom to minimize the cleanroom footprint of operations that would have previously taken place in a large ballroom. Media and buffer preparations, cell expansion, upstream, downstream and post viral are all housed in separate pods. The design minimizes fixed utility infrastructure and instead relies on single-use continuous upstream and downstream operations. 

Figure 1 shows the relationship between Cost of Goods Manufactured (COGM) of a therapeutic antibody, volumetric productivity and culture duration. The results indicated that COGM is strongly inversely correlated to volumetric productivity between titers of 0.5 and 3.0 g/L/day, as shown by the sharp drop in COGM with increased volumetric productivity. The inverse correlation is not as strong when comparing COGM and culture duration, which is likely because most of the cost reduction benefits are attained when the first few kilograms of product are manufactured (e.g., because of the high cost of shared downstream disposables). Marginal increases in culture duration will generate higher amounts of product and allow the production of metric tonne-quantities of antibody but are accompanied by a proportional increase in media and downstream buffer costs.

Figure 1. Sensitivity plot illustrating Cost of Goods Manufactured (COGM) versus bioreactor design variables. Color coding was used to layer in throughput as a measure of the three variables studied.

Expanding Access to Life-Saving Medicines

Just-Evotec Biologics has two facilities in North America that are operational and manufacturing biological medicines for clients. Our European facility will be brought online in Toulouse, France in late-2024. 

These facilities in two geopolitically stable locations will provide our customers with additional supply chain security. They feature our intensified manufacturing platform allowing the agile and low-cost production of biopharmaceuticals.

The cost-modelling described in this article shows the potential for the J.POD facilities to be capable of delivering metric-tonne quantities of biological medicines for late phase clinical and commercial manufacturing. Furthermore, it illustrates how the COGM decrease dramatically as titers increase so that extremely low production costs can be achieved. We believe that this provides an opportunity to reduce the overall costs of biological medicines and will allow patients around the world greater access to these life-saving medicines.

Read The Full Article

Cell line development at Just – Evotec Biologics is focused on lowering the cost of biologics development and manufacturing through the creation of highly productive engineered cell lines for our clients and partners. To achieve this, we leverage our own in-house GS knockout CHO host cell line, which has been shown to support cell densities up to 80 M cell/mL and productivities upwards of 5 g/L/day in our perfusion bioreactor platform. Additionally, we have implemented advanced instruments and liquid handling automation to increase the throughput of processes that are historically major bottlenecks. Examples of this include semi-automated, independent transfections of up to 32 different expression vectors or high throughput single-cell cloning/screening of up 1000 clones. Paired with our process development and manufacturing expertise, we continue to push the envelope on improving drug costs and have enabled many of our clients to file for INDs.

If you’d like to learn more about the benefits of a customized cell line development program, you can download our white paper here

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Patients around the world have limited or restricted access to biopharmaceutical medicines. Reducing production costs while still maintaining high quality standards will help increase the affordability of biologics and ensure more patients benefit from these life-saving medicines.

Traditional biomanufacturing facilities have failed to deliver biopharmaceutical products with sufficiently low Cost of Goods Manufactured (COGM) to allow greater patient access. These facilities have been built with fixed capacity and a focus on large-scale fed-batch manufacturing. Scaling-up processes to large-scale fed-batch manufacturing facilities involves considerable risk, resource, and upfront costs. Such facilities often lack flexibility which limits the products that can be produced within them and can leave valuable production assets idle for periods of time.

Manufacturing costs link directly to capacity utilization and product demand. There is a historical precedent within the biopharmaceutical industry of operating with excess capacity but we must recognise this comes with a financial penalty. We must address this challenge if we are to respond to global healthcare emergencies, changes in the way healthcare systems are managed and greater demand for global access to biotherapeutics.


Continuous Bioprocessing Platforms and Modular Facility Designs

The industry needs new flexible biomanufacturing concepts to quickly react to market fluctuations and achieve a higher predictability of costs. Modern biopharmaceutical productions facilities use building and manufacturing technologies, such as modular construction, to minimize clean room space utilization and reduce footprints. They allow faster speed to market with a lower upfront capital investment and are readily expandable when product demand is better understood. Continuous manufacturing platforms can be integrated into these facilities for low-cost bioprocessing using mammalian cell hosts in perfusion bioreactors linked to continuous downstream trains. Production costs remain low irrespective of facility mass output, the product quality attributes are consistent and manufacturing footprints are minimized.

Just-Evotec Biologics has developed a low-cost manufacturing facility design utilizing modular cleanroom pod technology that we call J.POD®. The J.POD facility design features individual pre-fabricated cleanroom pods arranged in a controlled, non-classified ballroom to minimize the cleanroom footprint of operations that would have previously taken place in a large ballroom. Media and buffer preparations, cell expansion, upstream, downstream and post viral are all housed in separate pods. The design minimizes fixed utility infrastructure and instead relies on single-use continuous upstream and downstream operations.

Biomanufacturing Facility Cost Comparisons

We developed process models for a fed-batch process in a traditional stainless-steel facility, a fed-batch process in a single-use facility and three continuous processes in a J.POD facility. The models were created using the Biosolve software (Biopharm Software Ltd) to show the benefit of the J.POD facility design on the COGM of an antibody biologic. We used Net Present Cost (NPC) to compare scenarios. NPC estimates cash flows by computing operational costs and discounting over time using a capital parameter. It does not include revenues in the accounting of cash flows and assumes capital costs are sunk costs incurred at the beginning of the project.



Figure 1 shows the expected costs from operating the different facility types and assumes their throughput increases at a rate of 250 kg/year up until a peak value. The range selected was representative of market demands for typical biopharmaceutical manufacturing facilities. Jumps in the NPC correspond to points when the capacity of a facility is reaches and new builds are needed.

We can draw the following conclusions from the results.

1. J.POD facilities achieve remarkable production outputs despite their small footprint because of the high productivity of the continuous perfusion process.
2. Fixed CapEx comprises a large proportion of the total costs in a stainless-steel facility. J.POD facilities apply single-use technologies resulting in a shift from fixed to variable costs.
3. The fully continuous J.POD facility gives the lowest costs with the stainless-steel facility returning the highest expenditure over the range.
4. The stainless-steel facility is not being operated at its optimum utilization rate over the production output range modelled that leads to inefficiencies.

Driving Up Access to Biotherapeutic Medicines

We believe that modern biomanufacturing facilities must have smaller processing spaces, higher production throughputs and lower production costs. Modelling shows how our J.POD facilities have the lowest initial build and operating costs as well as the ability to control operating costs. These facilities are outperforming older manufacturing platforms in terms of cost and utilization. They are becoming an essential component of strategies for reducing costs and driving up access to biotherapeutic medicines. 

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