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.

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How to optimize your hit identification strategy 

What is hit identification and why is it important?

Hit identification (Hit ID) is an important step in the development of new medicines. It is the process of identifying molecules with desirable biological activity, such as the ability to bind to the target and modify its function. As hit ID is one of the first steps in drug discovery, optimizing this process is essential to provide the best possible chemical starting points for your drug discovery and development process. A successful hit ID campaign will maximize the output in terms of the number of high-quality hits that enter the hit-to-lead and lead optimization stages, saving you precious time and resources further down the line. 

However, identifying high-quality, validated hits is no easy feat. There are several components of hit ID campaigns that need to be considered, including the selection of the compound library, and the development of pharmacologically sensitive and robust assays for screening, triage, and validation. Hit ID also requires a broad interplay of disciplines, like reagent production, in vitro biology, medicinal chemistry, and statistical data analysis. These interact across several approaches, such as target-directed, structure-based, in silico, and phenotypic hit ID. With this in mind, extensive multi-disciplinary expertise is applied to design and implement the right hit ID campaign for your target.

To help simplify this pivotal stage in the drug discovery process and ensure that you get the most high-quality hits for your target, here are our top considerations for hit ID campaigns. Across those, we explore how an integrated end-to-end platform is key to supporting all stages of the hit ID process, and beyond.

Considerations to help you optimize your hit identification campaign

Screening strategies

There are several well-established screening approaches for hit ID, including target-directed, structure-based, in silico, or phenotypic high-throughput screening routes. Different approaches can be run in parallel or individually, depending on your target.  

Choosing the right screening strategy is one of the most important considerations for the hit ID process, and will largely determine the success of your campaign. To learn more about the different screening approaches, visit our hit identification webpage.  

Assay development

Primary assays are used for the detection of on-target activity or binding in high-throughput screens. There are different types of primary assays, such as cell-based, or biochemical assay systems. While cell-based assays provide a more physiologically relevant context, biochemical assays can give you deeper insight into target binding or modulation of the target’s function in a cell-free environment. Therefore, the type of assay you choose depends on your target, and the specific goals and requirements of your campaign. Visit our in vitro biology webpage to learn more about the different phenotypic and cellular-based assay technologies. 

When optimizing primary assays, it is important to verify the relevance of the assay to your specific disease state and target. Additional factors such as robustness, pharmacological sensitivity, reproducibility, scalability, and cost efficiency are taken into account. Development of such primary assays can be a complex and lengthy process that involves many steps, from initial setup, optimization, and pharmacological characterization, through to the adaptation to the screening system and pre-screening.

Further to the primary assay, the development of an appropriate readout counter assay is strongly recommended. Such assay applied at later stages of the screening process enables the identification of potential readout-interfering compounds that could result in false positive hits.

Compound libraries

Compound libraries are collections of small molecules used to identify hits in high-throughput screening assays. The success of your hit ID campaign relies heavily on your chosen compound library. To maximize your chances of success, such compound libraries should consist of highly attractive, chemically diverse compounds with proven lead-like properties, but also good solubility and stability. Thus, quality, size, and diversity of the compound collection will impact the success of your hit ID campaign.  

In high-throughput screens, large libraries of several hundreds of thousands of compounds are screened to cover as much of the available chemical space as possible. However, in specific cases, a more tailored screening approach might be more appropriate, using a smaller, either diverse, or focused compound library.  

Screening and hit triaging

The screening process involves several steps, starting with a pilot screen using a representative subset of the screening collection. Upon definition of the final screening conditions including the compound concentration, the primary screen is then performed on the selected screening deck. The primary hits identified are confirmed by testing them again in replicates before the final step of concentration-response profiling is started. 

The concentration-response relationship of confirmed hits is tested against the primary assay and the readout counter, as well as against relevant selectivity targets, if applicable. A diligent, data-driven analysis of the results, involving a medicinal chemistry review and assessment, enables the prioritization of compound series with both a desired biological profile and attractive chemistry.  

Figure 1. A typical hit ID workflow, illustrating the various steps involved in high throughput screening and hit triaging. 

Hit validation 

Following hit triage, prioritized hit series are validated to confirm their biological activity through the application of secondary assays. These are carried out using orthogonal readouts like biophysical methods to confirm on-target activity, or are conducted in more physiologically relevant systems like cell-based assays. Secondary assays are used to assess several crucial properties of the hits, including functional response.  

Medicinal chemistry efforts during hit validation focus on the analysis of the hit’s structure-activity relationship (SAR). Such analysis aims to identify the structural elements that are associated with its biological activity. To further the assessment of on-target activity and selectivity, additional in vitro assays are commonly conducted at this stage. These evaluate the absorption, distribution, metabolism, and excretion (ADME) properties of the hits. You can visit our DMPK and ADME-Tox webpage to read more about secondary ADME-Tox assays for hit validation. 

Using all this information together, the hit series that will progress to the hit-to-lead phase are identified. The number of series that are taken forward will depend on resource availability, although around two to three hit series are usually recommended. 

Mastering hit identification  

When optimizing your hit ID campaign, there are many factors to consider, including the quality of your compound library, and the strategies for primary screening, triage, and validation. The most successful hit ID campaigns implement a data-driven approach that utilizes techniques across a broad range of disciplines, including biochemistry, computational chemistry, in vitro biology, and medicinal chemistry.  

Figure 2. A checklist for successful hit ID campaigns, from screening strategy through to hit validation, to help you increase the number of high-quality hits obtained. 

View our webinar to learn more about the essential considerations for successful hit identification by high-throughput screening, including planning, compound collections, infrastructure, assay formats, and the benefits of an interdisciplinary approach. 

Externalizing your hit identification 

At Evotec, we provide industry-leading hit ID services through our decades of experience, state-of-the-art screening technologies, and a diverse, high-quality compound collection. This utilization of a broad range of expertise, facilities, and technologies takes away the stress of hit ID, minimizing the risks of attrition, and even allowing you to hit previously undruggable targets.  

When partnering with Evotec, our expert screening team will help you design and conduct a bespoke hit ID campaign that is optimized for your target, giving you the best possible chemical starting points. And once the best hit series for your target have been identified, our integrated, end-to-end R&D platform can support you from drug discovery, right through to drug development and manufacture, helping you get your drug to market in the simplest, most time, and cost-effective manner. 

For more information on our hit ID services, and to learn how we can support your projects from concept to clinic, visit our website.

Visit our website

Also, join our ongoing webinar series on accelerated hit identification through innovative high throughput screening approaches.

Join the webinar series

Date: March 17-21

Location: New Orleans, LA 

Attending

• Chaz Goodwine, Senior Scientist I at Just-Evotec Biologics
  
  

Presenting

Poster Title: Development of Single Pass Tangential Flow Filtration for Continuous End-to-End mAb Bioprocessing

Presenter: Chaz Goodwine, Senior Scientist I at Just-Evotec Biologics

Where: at the BIOT Poster Session

When: March 19

Join us at the ACS BIOT event where Chaz Goodwine, Senior Scientist I at Just-Evotec Biologics will be chairing the BIOT Division's session "Chromatographic separations using novel stationary phases and approaches". 

Where: Gravier C Ballroom

When: March 20, 9:00 am- 10:00 am

Learn more about ACS BIOT

“The intracellular exchange assay design enables studying the cumulative effect of modulators from the intracellular face of ion channels.” 

Background:

Intracellular binding sites of ion channels are targets for many drugs (example: anesthetics targeting voltage gated sodium channels). Pharmacological manipulation of the intracellular (IC) environment is as critical as the extracellular (EC) environment.  

In manual patch clamp, once the gigaseal is established and the patch is in whole cell mode, manipulating the IC environment by pipette solution exchange is a technical feat few can achieve (reference).  

This is where the intracellular exchange (ICE) assay developed by Evotec on Sophion Qube changes the game. 

The assay design: 

As is illustrated below (fig. 1), an EC salt solution is added to each well in a 384-well QChip via an inlet well and the same can be removed via a waste well, both from the top (fig. 1). On the other hand, the IC salt solution has only one inlet/outlet channel i.e. for both perfusing in and out. 

In the ICE assay, cells are patched on this QChip in the whole-cell mode using a negative pressure via the patch hole. The cells are thus surrounded by the EC solution while the cytosol is accessed via the IC solution.  

Figure 1: Architecture of each well in a 384-well Qchip (left). A single hole Qchip with the indicated intracellular (IC) solution inlet.

Hereafter, the magic begins: after one or more stabilization stages to obtain baseline activity, the IC solution is completely replaced with a new IC solution in sequential liquid periods. Our ICE assay has been developed to execute such IC exchanges up to four times (fig. 2), replacing the previous solution completely with a new solution each time.  

Figure 2: Liquid periods in the ICE assay with the stabilization periods to obtain baseline activity followed by four rounds of IC solution exchange. 

Thus, modulators can be delivered to the cytosolic face of the ion channel cumulatively.  

All the while, the cells are maintained in whole cell configuration in the QChip and the seal resistance does not drop below the QC threshold (40 MΩ, fig. 3). The ion channel target is observed to respond to each increasing concentration of the modulator post-exchange (fig. 3). 

Figure 3: (a) Seal resistance during sequential liquid periods interspersed with removal of the Qchip from the bio-chip interface, (b) Current vs time (IT) plot. Signal from the target ion channel responds to cumulatively increasing concentration of the modulator in cytosolic side. 

Achieve more with less reagents and resources: 

• With four rounds of exchange, the volume of the IC solution required is only 4 ml for 3-4 experiments.  
• The assay has a throughput of up to 26 compounds per Qchip for a 3-point dose response profiling.  
• The assay is very resource-friendly also in terms of chemistry, since only minute amounts of compound are required. 
• An experiment with four exchanges lasts only about 90 minutes.  

In a proprietary assay developed by Evotec, it was possible to profile about 700 compounds in 70 runs performed over 64 days.  

Key learnings: 

• The IC exchange assay can cumulatively test three increasing concentrations of the same compound, delivered to the cytosolic face, providing pre- and post-compound data.  
• A complete solution exchange is possible between each concentration, thus preventing compound cross-contamination.  
• The assay can also be adapted to different intracellular ion concentrations, pH values, or signaling molecules.  
• Druggability of ion channels as a family of proteins is greatly enhanced. 

No matter whether your drug discovery program is in the hit ID, hit-to-lead, lead optimization or early safety assessment, the ICE assay is useful for high-throughput hit profiling at any point.  

Companies interested in using Evotec’s technology are welcome to contact Evotec at info@evotec.com. 

Evotec possesses a comprehensive drug discovery platform to support oligonucleotide-based drug discovery from in silico design to clinical translation. Oligonucleotides therapeutics have been emerging as novel therapeutic modality for a vast range of diseases constantly growing resulting in 15 drugs currently approved. Here, we show our ongoing effort to further expand this platform by employing the recently developed splintR-qPCR as a novel bio-analytical method for quantification of oligonucleotides in tissues and comparing it to LC/MS and bDNA in use in Evotec. Within an Evotec internal R&D proof of concept study, the splintR-qPCR was proven as valid and comparable method to bDNA and gold-standard LC/MS. The high sensitivity, throughput and low costs compared to LC/MS and bDNA assay place splintR-qPCR as pivotal method that will strengthen Evotec oligonucleotides expertise on PKPD modelling.

Download our poster here!

Presentation slide deck for the webinar Deciphering the Clinincal DDI Between Atazanavir and Rosuvastatin.