Transitioning to continuous manufacturing for commercial biologics production

Transitioning to continuous manufacturing for commercial-scale biologics production represents a significant – but highly beneficial – shift in biomanufacturing strategies. This approach not only promises reduced costs, enhanced efficiency, and productivity, but also ensures consistent product quality ¹.

As part of this three-part blog series, we’ve previously covered the current issues faced in biologics production, and how continuous manufacturing helps to address these. In this final blog of our series, we delve into the steps required to transition from traditional fed-batch processes to continuous manufacturing, focusing on feasibility, commercial process development, and process validation.

Assessing feasibility

The first step in transitioning to continuous manufacturing is a thorough 3-month feasibility assessment. This involves evaluating the existing fed-batch process and identifying potential challenges and opportunities for continuous operation. Just – Evotec Biologics leverages its extensive expertise in continuous manufacturing to conduct detailed feasibility studies, which include:

• Cell line assessments: We run ‘mock perfusion’ cultures in scale-down models with existing or new cell lines and assess growth, productivity, and product quality.
  
  
• Verification at 3L bioreactor scale: The most promising cultures from the cell line assessments are re-run at the 3L scale and the perfusate used to screen downstream platform conditions using high-throughput technologies.
  
  
• COGM modeling comparison: Our experts compare data from the fed-batch performance with those generated during the feasibility study. This allows for an evaluation of the COGM benefits of switching to our continuous manufacturing platform.

Intrigued about how our feasibility studies are conducted? Uncover further details here

Figure 1: Timeline of a minimally resourced, 3-month feasibility study, demonstrating margin gains, reduce risk, and validate ROI assumptions

The COGM models used in our feasibility studies are based on Net Present Costs (NPC). NPC calculations estimate cash flows by calculating operational costs and discounting over time using a cost of capital parameter ². We use these models to compare the COGM for continuous manufacturing with existing fed-batch processes, across different post-launch demand situations. Continuous manufacturing in J.POD^® facilities typically show lower operational costs, irrespective of production rates, due to our flexible facility design ². 

Check out our previous blog to learn how continuous manufacturing can lower biologics production costs by 75 %  

Commercial process development

Once feasibility is established, the next step is to develop a robust, scaled-up commercial process. This involves:

1. Establishing a full 25-day end-to-end continuous manufacturing process: Establishing a continuous manufacturing process and evaluating robustness over a 25-day process, to ensure the biologic’s product quality attributes (PQAs) are maintained for the duration of the run.
   
   
2. A 1000-L engineering run: At our innovative cGMP facility , a commercial-scale run is conducted to demonstrate process efficacy
   
   
3. Clinical manufacturing runs: Supply subsequent clinical trials. Material is taken from these runs to generate and qualify the reference standard and perform stability studies on the drug substance (DS), ensuring regulatory compliance and future commercial success

 

During this development stage, we ensure the process is robust and can be seamlessly scaled up to meet commercial production demands. Our J.POD^®  facilities are designed to be highly adaptable, and enable a flexible process that can quickly adjust to changing market demands. Working together with our partners, we refine the continuous manufacturing process to maximize yield, productivity, and product quality.

Process validation

The final step in the transition is process validation. We perform process characterization, process validation and other Biologics License Application (BLA)-enabling studies. These include facility risk assessments, DS freeze/thaw studies, as well as shipping validation assessments.

These studies are critical for regulatory compliance and ensure consistent product quality ³. Ensuring the process meets all regulatory requirements, Just – Evotec Biologics has extensive experience in navigating regulatory landscapes, facilitating a smoother approval process.

Step into the new era of biologics manufacturing

Transitioning to continuous manufacturing is a transformative step for commercial biologics production. It offers significant benefits, including cost reduction, enhanced efficiency, and improved product quality. The additional advantage of our short feasibility studies is that they allow for the potential benefits of transitioning to be evaluated prior to committing to a full transition, substantially reducing risks. By leveraging advanced technologies and expert guidance from Just – Evotec Biologics, biopharma companies can successfully navigate this transition, stepping into the new era in biologics manufacturing.

Proven expertise in commercial manufacturing

At Just – Evotec Biologics, we wield our expertise to focus on developing and manufacturing antibody and antibody-related products, as well as biologic formats expressed in Chinese Hamster Ovary (CHO) cells. The company has demonstrated its cGMP manufacturing success over the past ten years. We provide support filing BLAs and Investigational New Drug (IND) applications. Having surpassed several cGMP compliance milestones, across the US, Canada, and the UK, Just – Evotec Biologics is positioned as a trusted global partner in the journey towards making life-saving therapies accessible worldwide.

Find out how Just – Evotec Biologics can elevate your biomanufacturing processes

References

1. From Development to Delivery: How Continuous Manufacturing is Redefining the Commercial Landscape for Biologics - Science Pool. Available at: https://sciencepool.evotec.com/from-development-to-delivery-how-continuous-manufacturing-is-redefining-the-commercial-landscape-for-biologics/ Accessed 11 August, 2024
2. Garcia, F.A. and Gefroh, E. Reducing biopharmaceutical manufacturing costs through continuous processing in a flexible J.POD^® facility. Drug Discovery Today. (2023); 28(7):103619. https://doi.org/10.1016/j.drudis.2023.103619 
3. Modality Solutions, Battista R. Unlocking FDA Insights: Open Data Files for Successful BLA Submissions. Available at: https://www.modality-solutions.com/unlocking-fda-insights-open-data-files-successful-bla-submissions/ Accessed 11 August, 2024

 

Did you know that cold storage units, particularly ultra-low temperature (ULT) freezers installed in our laboratories use an incredible amount of energy? In fact, just one ULT freezer can consume as much energy as an average family home.

To address this, Evotec signed up to The International Laboratory Freezer Challenge - a partnership project between My Green Lab and the International Institute for Sustainable Laboratories (I2SL). The competition is run annually from January to July and is designed to promote best practices in cold storage management within laboratories. Not only does the initiative contribute to environmental sustainability by saving energy within the laboratory but businesses also benefit by reducing their energy bills.  

At Evotec alone, 32 teams across 10 global sites embarked on this challenge in 2024.  Overall, the company has saved an incredible 1325.65 kWh/day (483,862 kWh/year) which is equivalent to the energy consumption of 53 family homes, 334 metric tons of carbon dioxide or 80 gasoline powered cars driven for one year. To reward the achievement, Evotec received an Honourable Mention for its role in this worthwhile project. 

So how did we achieve this? 

Due to the size and worldwide presence of Evotec, successful management of the project was key to its success. Global participation in the initiative was co-ordinated by sustainability champion, Maya Farah, and was supported by the ESG department. Each team was assigned a local sustainability champion who - along with freezer challenge site co-ordinators and department representatives - shared tips, insights and achievement to keep the challenge spirit alive.

Most of the improvements were gained by establishing cold storage best practices such as:
•    defrosting freezer units
•    cleaning filters, coils and intakes
•    brushing frost from cabinet and door seals
•    updating inventories and discarding samples no longer needed
•    retiring older inefficient cold storage units and investing in energy efficient upgrades
•    sharing cold storage space
•    barcoding inventories
•    adjusting ULT freezer setpoints where feasible

Cumulatively, in 2024, the International Laboratory Freezer Challenge saved a record breaking 31.8 million kWh of energy saving which translates to the equivalent of 22,000 metric tons of carbon dioxide and 5296 gasoline powered passenger vehicles driven for one year.

Volker Braun, EVP Head of Global Investor Relations & ESG, commented on Evotec’s achievement, ‘It is exceptionally motivating to see how all the teams have worked so hard for this challenge. Our local sustainability champions have proactively applied internationally recommended best practices, which sets an example to all teams within the company and enables a work culture of continuous improvement. Their actions have significantly reduced Evotec’s energy consumption and carbon footprint helping to contribute to a more sustainable world.’

It should be remembered that the International Laboratory Freezer Challenge forms only a small part of the overall sustainability goals for Evotec. The company has committed to reach net zero greenhouse gas (GHG) emissions by 2045, reduce scope 1 and 2 GHG emissions by 50.4% by 2032 and by 95% by 2045 (from a 2021 base year), and increase active annual sourcing of renewable electricity to 100% by 2026. Furthermore, we aim to reduce scope 3 GHG emissions from purchased goods and services and capital goods by 72% by 2032 and commit that 80% of Evotec’s suppliers will have science-based targets by 2027.

Evotec’s latest sustainability report details its ESG commitments.

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In the complex world of biopharmaceutical development, Chemistry, Manufacturing, and Controls (CMC) activities are critical yet often fraught with challenges. Just-Evotec Biologics offers a suite of innovative solutions designed to mitigate these risks, with their J.MD™ Molecular Design service standing out as a key player in this arena.

 

The Role of J.MD™ Molecular Design

The J.MD™ Molecular Design service is part of Just-Evotec Biologics’ comprehensive J.DESIGN™ platform, which integrates advanced computational tools and high-throughput methodologies to streamline the development process. This service focuses on selecting an optimal lead and optimizing the molecular design of biologics to ensure manufacturability, stability, and efficacy from the earliest stages of development.

 

Evaluating Early Team Supply Material

One of the primary ways J.MD™ helps derisk CMC efforts is by evaluating early team supply material produced in stable pools. This early biophysical characterization is crucial for identifying potential issues that could arise later in the development process. By addressing these issues upfront, Just-Evotec Biologics helps partners avoid costly and time-consuming setbacks.

 

Derisking the CMC Journey

The CMC journey involves numerous stages, from initial development to production-scale manufacturing. Each stage presents unique challenges that can impact the overall success of a biopharmaceutical product. Just-Evotec Biologics’ J.MD™ service helps derisk this journey in several ways:

• Predictive Computational Tools: The Abacus™ tool within the J.MD™ toolbox uses predictive algorithms to assess the manufacturability and stability of different molecular variants. This allows for the selection of lead candidates with optimal properties, reducing the risk of failure in later stages¹.

 

• High-Throughput Screening: By leveraging high-throughput screening methods, J.MD™ can rapidly evaluate multiple variants, accelerating the development timeline and ensuring that only the most promising candidates move forward².

 

• Integrated Development Approach: The J.MD™ service is part of a larger, integrated approach that includes cell line development, process optimization, and continuous manufacturing. This holistic approach ensures that all aspects of the CMC process are aligned and optimized for success³.

 

• Regulatory Support: Just-Evotec Biologics also provides comprehensive regulatory support, helping partners navigate the complex landscape of biopharmaceutical regulations. This support is crucial for ensuring that products meet all necessary standards and can be brought to market efficiently⁴.

 

Conclusion

In summary, Just-Evotec Biologics’ J.MD™ Molecular Design service plays a pivotal role in derisking CMC efforts for biopharmaceutical partners⁵. By evaluating early team supply material, leveraging predictive computational tools, and integrating a comprehensive development approach, J.MD™ helps ensure that the CMC journey is as smooth and successful as possible. This not only saves time and resources but also increases the likelihood of bringing effective and safe biopharmaceutical products to market.

 

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References

1. Just-Evotec Biologics’ Abacus™ tool 
2. High-throughput screening methods
3. Integrated development approach
4. Regulatory support
5. Derisking CMC efforts for biopharmaceutical partners

Cardiotoxicity is defined as toxicity that affects the heart. Drug-induced cardiotoxicity remains an important cause of pre-clinical and clinical drug failure. At Cyprotex, we are developing cutting-edge strategies to effectively predict toxicities at an early stage in the drug development process to guarantee the progression of safe novel pharmaceuticals and reduce later-stage attrition.

The mechanisms by which drugs can induce cardiotoxicity are diverse, ranging from functional (acute alteration of the mechanical function of the myocardium) to structural impairment (morphological damage to cardiomyocytes), and the clinical manifestations are wide-ranging, spanning from arrhythmia to myocardial dysfunction, to terminal heart failure. Cardiotoxicity generally results from the disruption of key cardiomyocyte processes affecting contractility, electrophysiology (ion channel trafficking), mitochondrial function, growth factors and cytokine regulation. Consequently, our assays have been developed to cover various readouts by combining multiple approaches to obtain a complete understanding of toxic effects.

At the 58^th Congress of the European Societies of Toxicology (Copenhagen, Eurotox 2024), we presented our latest work in cardiotoxicity prediction in the form of a poster, titled: “High-throughput transcriptomics combined with in vitro assays for cardiotoxicity risk assessment and mechanistic understanding”. Here, we investigated the effects of 148 reference compounds, (including structural and/or functional cardiotoxicants as well as non-cardiotoxicants) on human induced pluripotent stem cell derived cardiomyocytes (hiPSC-CMs) using high-throughput transcriptomics assessing the entire transcriptome (HT-transcriptomics), high-content imaging (HCI) and kinetic monitoring of calcium transients (CaT). Our compound set covered a broad range of mechanisms of action including ion channel inhibitors (Na⁺, K⁺, Ca²⁺), receptor modulators (adrenergic, dopamine, serotonin, histamine, acetylcholine, glucocorticoid, sulfonylurea), enzyme activities (COX, phosphodiesterase) and DNA metabolism.

Calcium transients, assessed by fast kinetic fluorescent readings, allowed a series of Ca²⁺ peak parameters to be studied including amplitude, frequency, full rise and decay time and peak width, which taken together revealed the effects of compounds on cardiomyocyte contraction. Since the calcium transients are closely associated with muscle contraction and ventricular action potentials, they can help us understand the in vivo cardiotoxicity effects of some compounds including electrocardiogram alterations such as QT interval prolongation. Additionally, HCI was used to assess any structural damage to the cardiomyocytes upon analysis of nuclei impairment, calcium homeostasis and mitochondrial function. Finally, HT-transcriptomics shed light on the transcriptional responses triggered upon compound treatment, which were further analysed for pathway enrichment and differential gene expression.

This multi-parametric approach allowed the identification of the readout showing the lowest minimum effective concentration (MEC). Compounds were then classified as cardiotoxic if the MEC value was below a specific maximum plasma concentration (C_max) threshold calculated using in vivo literature cardiotox classifications. Additionally, AI/Machine Learning (ML) models were developed to predict cardiotoxicity using a 20x C_max threshold and a tox score threshold. This allowed the classification of compounds as cardiotoxic if the true C_max (historical in vivo response) was above the predicted safe C_max, giving excellent prediction metrics with 78.7% sensitivity, 86.7% specificity and 81.4% accuracy.

Finally, testing dynamic C_max thresholds and different assay combinations proved useful to effectively predicting cardiotoxicity risk with excellent accuracy, whilst assigning more weight to specificity over sensitivity to avoid losing valuable drug candidates due to false-positive risks. The best predictions were achieved by combining HT-transcriptomics AI/ML modelling (20x C_max), HCI (1x C_max) and CaT (2x C_max) endpoints, with 85.9% sensitivity, 84.1% specificity and 85.3% accuracy.

Future work will involve further expansion of our reference compound list to cover an even larger range of mechanisms and chemical space, and to explore the transcriptomics pathway endpoints by performing a Point of Departure (PoD) using Benchmark Dose (BMD) analysis approach, for both hiPSC-CMs and organotypic 3D models which are likely to be more representative of the in vivo tissue structurally and functionally.

Interested in learning more?

Contact us to discuss your project.

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In the evolving landscape of cancer treatment, Immuno-Oncology (IO) has been at the forefront for the past 15 years, revolutionizing our approach to battling this formidable disease. Immunotherapy, which harnesses the body's immune system to fight cancer, offers hope where traditional therapies have often fallen short. For instance, in advanced stage IV melanoma, the median survival has improved from 6 months to 6 years over the past decade thanks to immunotherapy.

However, the journey from discovery to clinical application is fraught with challenges. Why do some patients respond to immunotherapy while others do not? What opportunities exist for developing the right combination therapies? How can we better select the right cancer indications for a particular IO target? How can we ensure the success of these treatments across diverse patient populations?

At Evotec, our immunologists are equipped with the expertise and experience to support your IO projects from target identification through to clinical trials. Whether you require a comprehensive and strategic partnership or targeted support at critical stages, our capabilities can synergize with your efforts to make a tangible difference.

Comprehensive Support Across the Immuno-Oncology Spectrum

In-depth Immunology Expertise

Our team’s knowledge spans from innate to adaptive immunity, providing a robust foundation for developing cutting-edge cancer immunotherapies. We offer:

●    Genetic Engineering of Primary Immune Cells: Optimizing target validation for effective therapy development.
●    Bespoke In Vitro Immunological Assays: Custom-designed assays to evaluate immune responses and the potency of immunotherapeutic candidates.
●    Single-Cell Level Immunotherapy Assessment: Utilizing Immunological Synapse technology for precise drug discovery.

Preclinical Animal Models Dedicated to IO

Moving forward with candidates within the drug discovery journey requires robust and tailored in vivo models for IO:
●    Syngeneic Mouse Models: Developed with various tumor-immune phenotypes and responsiveness to checkpoint inhibitors; these models help in assessing therapeutic efficacy, modulation of the immune response (tumor microenvironment and periphery), as well as pharmacodynamics features (PK/PD).
●    Humanized Mouse Models: Presenting a functional human immune system with the possibility of xenografting a human tumor. These models are pivotal for particular therapeutic modalities such as biologic therapeutics (e.g., immune cell engagers) or cell therapies; they could also be interesting for early toxicology studies looking at immune-related adverse events.

Translational Validation Using Relevant Patient Samples

To bridge the gap between in vitro models done with primary human immune cells isolated from healthy donors and in vivo models in the drug discovery process:
●    Broad Clinical Network: Collaborations with hospitals and clinicians to select the relevant samples for the project.
●    Translational Validation of Therapies: Access to cancer patient samples ensures that therapies are effective in a patient context.
●    Enhanced Target Validation: Possibility to develop on-target biomarker assays or validate target expression in a particular indication.

Advanced Technological Integration

Our approach integrates cutting-edge technologies to de-risk your drug development strategy:
●    High-Throughput Imaging and Analysis: Tools like the ImageStream X and Operetta provide high-speed, high-resolution insights into immune cell interactions.
●    Complex Flow-Cytometry and Functional Assays: These analyses on fresh human tumor samples facilitate target engagement validation and biomarker identification.
●    Omics Technologies: Including scRNAseq, TCR sequencing, and proteomics, to uncover novel biomarkers and therapeutic targets.

Precision Medicine and Biomarker Strategies

By incorporating biomarker strategies early in the discovery process, we enhance the understanding of disease mechanisms and improve patient stratification for clinical trials. Our efforts in precision medicine are aimed at identifying the right therapeutic interventions for the right patients, thereby increasing the likelihood of clinical success.

The Evotec Advantage

Evotec’s experienced IO team supports your projects from the lab bench to the patient bedside. Our comprehensive services include:
●    Functional In Vitro Immunological Assays: Supporting programs for small molecules, biologics, and cell therapies.
●    In Vivo Rodent Models: Essential for preclinical testing of therapeutic efficacy and safety.
●    Translational Research and Patient Sample Access: Enhancing the relevance and translatability of preclinical findings.

Driving Success in Immuno-Oncology

Our integrated approach, combining deep immunological expertise with advanced technologies and translational capabilities, ensures that we address the complex challenges of IO drug discovery. By partnering with Evotec, you gain access to a wealth of knowledge and resources designed to propel your project forward, from the initial stages of discovery to the clinical validation of novel therapies.
For more information on how Evotec can support your Immuno-Oncology projects, visit our website or contact us at info@evotec.com.

Conclusion

The revolution in cancer immunotherapy is just beginning, and the journey to effective treatments requires collaboration, innovation, and expertise. At Evotec, we are committed to advancing the field of Immuno-Oncology, providing the tools and support necessary to transform groundbreaking discoveries into life-saving therapies. Join us in this mission and let’s make a difference in the fight against cancer.
Contact us today to speak with one of our immunologists and explore how we can progress your IO projects together.

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In the dynamic world of biopharmaceuticals, cost efficiency is a critical factor, especially for start-up companies navigating the complex landscape of drug development. Continuous biomanufacturing is an innovative approach that has garnered significant attention for its potential to significantly reduce the cost of commercial biologics. Less often discussed, however, is the potential for continuous biomanufacturing platforms for first-in-human (FIH) clinical trials. This method not only streamlines the production process but also offers substantial savings during the manufacture of material intended for early phase antibody development, making it an attractive option for emerging biotech firms.

 

What is Continuous Biomanufacturing?

Continuous biomanufacturing is a process where the production of biopharmaceuticals occurs in a seamless, ongoing manner, as opposed to traditional batch manufacturing, which involves discrete, separate production cycles. This continuous approach leverages advanced technologies and automation to maintain a steady flow of production, ensuring consistent quality and efficiency.

 

Cost Efficiency in Early-Stage Clinical Trials

One of the most compelling advantages of continuous biomanufacturing is its ability to produce large quantities of biopharmaceuticals in a single run. This is particularly beneficial for early phase clinical trials, where the initial supply can often be enough to cover subsequent Phase 2a and Phase 2b clinical studies. Here’s why emerging biopharmaceutical companies benefit:

1. Elimination of Additional Batches: Traditional batch manufacturing often requires multiple production runs to meet the demands of Phase I and II clinical trials. Each additional batch incurs significant costs, including raw materials, labor, and quality control. Continuous biomanufacturing, however, can produce a large enough supply in one go, eliminating the need for these extra batches.
   
   
2. Consistent Quality: Continuous processes are designed to maintain a high level of consistency and offer more levers to tightly control critical quality attributes than fed-batch processes. Supplying multiple clinical trials from the same lot of material ensures a perfect level of consistency which is crucial for regulatory approval and patient safety, further streamlining the development process.
   
   
3. Time Savings: By producing all necessary material in one continuous run, companies can significantly reduce the overall time required to manufacture the material they need for clinical trials. They avoid the challenge of finding available slots in their CDMO’s production schedule. This accelerates the overall timeline for clinical trials, allowing for faster progression through the development pipeline.

 

Financial Impact for Start-Ups

For start-up companies, the financial implications of continuous biomanufacturing are profound. The cost savings from eliminating additional batches can amount to millions of dollars. These funds can then be redirected towards other critical areas of drug development, such as:

1. Research and Development: Investing in expanding the pipeline of new candidate biopharmaceuticals. 
   
   
2. Clinical Trials: Initiating additional clinical studies for other disease indications. 
   
   
3. Extending the funding runway: Providing the company with the longest possible time before it needs to raise additional funding. 
   
   

 

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From Batches to Brilliance: The Benefits of Continuous for Commercial Manufacturing

As we covered in the first blog of this series,  biotherapeutics sponsor companies face numerous challenges in process development and manufacturing. This largely comes down to the overwhelming reliance on fed-batch processes in the biologics industry, which bring lengthy production timelines, process risks, and supply chain vulnerabilities. These issues contribute to the high cost structure of biologics and limit the accessibility of these vital therapies worldwide.

Continuous manufacturing is a rapidly emerging alternative production process to fed-batch processing. Biological products are produced in an uninterrupted flow, resulting in a steady and consistent output of product. This approach addresses many of the challenges with fed-batch systems, including: 

• Reduced process costs and lower cost of goods manufactured (COGM)
• Scalability and adaptability to fluctuating demands
• Fewer process and scalability risks

Read on as we explore these benefits of continuous manufacturing for commercial manufacturing, describing how they can address the high cost structure associated with biologics, and help to meet the rising global demand for these life-saving therapies. 

 

Cost reduction

Continuous manufacturing can reduce the COGM by up to 75% compared to traditional fed-batch processes (1), while also achieving 10-fold higher productivity (Figure 1). 

Figure 1: Productivity of a fed-batch process compared with a continuous approach. 

 

This is partly achieved through workflow automation, which minimizes labor costs while improving production efficiency (Figure 2). Additionally, compared with fed-batch units that require large facilities to store product intermediates, continuous operations are highly intensified and have a much smaller facility footprint, further reducing operational costs. Continuous operations also enable manufacturers to optimize resource use and reduce waste, leading to additional cost savings. 

Figure 2: Unit operations and labor resources needed to run a continuous process compared to traditional fed-batch process

 

Scalability and adaptability

A continuous approach allows for a much more agile process, driven by greater scalability and adaptability. For instance, J.POD^® biomanufacturing facilities from Just – Evotec Biologics support throughput from less than 10 kg to over 2,000 kg per year of protein-based biologics including mAbs and biosimilars. Production can be rapidly scaled up by increasing bioreactor numbers and extending run times with intensified continuous manufacturing technology. This enables manufacturers to adjust production levels quickly in response to market demand. 

Figure 3: How Just – Evotec Biologics’ platform steady-state intensified continuous manufacturing process can be scaled

 

Reduced risk

Continuous manufacturing reduces risks by ensuring consistent product quality. A DoE approach can be used to fine tune product quality attributes (PQAs) during development and advanced monitoring in production can maintain process consistency. This consistency is crucial for reducing regulatory risks and ensuring the efficacy and safety of biologics. 

This innovative manufacturing approach also enhances supply chain and financial security. With a smaller facility footprint and reduced operational costs, the financial risk for sponsor companies is substantially reduced. The modular design of facilities like J.POD allows for rapid deployment and scaling, mitigating geopolitical disruptions and financial risks associated with traditional fed-batch processes.

Making the transition is easier than you think. Explore the benefits and the process in more detail in our whitepaper

 

Unravelling the blueprint for success 

Transitioning to continuous manufacturing for commercial supply, in modular facilities like J.POD, offers a robust, cost-effective, and adaptable solution to address the unmet demand for biologics globally. Yet despite the clear benefits of continuous manufacturing, many manufacturers have yet to make the transition from fed-batch systems. This is often due to a lack of understanding of regulatory uncertainties, deployment pathways, and process development activities. 

Just – Evotec Biologics leverages over a decade of expertise in continuous manufacturing to help clients convert their fed-batch processes to its continuous manufacturing platform ready for commercial production. Commercial supply runs with its continuous manufacturing platform can be performed within one of its J.POD biomanufacturing facilities. These modular, scalable facilities are designed to offer the following benefits: 

• Maximized yields and cost efficiency – J.POD facilities utilize intensified continuous perfusion culture supporting high cell densities and product yield. The facilities also minimize operational costs through workflow automation, intensified bioprocessing, optimized resource use, and more.

• Rapid deployment and advanced agility – J.POD facilities are built using modular cleanroom pods that can be swiftly deployed and assembled. This design allows for flexible and scalable manufacturing capacity, enabling the facility to adapt quickly to changing production needs.

• Risk resilience – With established facilities in the US and Europe, J.POD mitigates the risk of geopolitical or supply disruptions. These facilities are standardized in design and operation, allowing for seamless process transfer between sites. 

 

Discover the full benefits of J.POD facilities 

 

References

1. Garcia, F.A. and Gefroh, E. Reducing biopharmaceutical manufacturing costs through continuous processing in a flexible J.POD® facility. Drug Discovery Today. (2023); 28 (7): 103619. https://doi.org/10.1016/j.drudis.2023.103619 

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)

 

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With active partnerships across 3 continents with more than 40 top-tier academic partners and a diverse cohort of investors, Evotec’s BRIDGEs have become a globally leading pre-seed accelerator initiative.

Alongside operational BRIDGE-building, our team has also been reflecting conceptually on the challenges and best practices in accelerating the transition from an academic starting point in drug discovery to an investable proof of concept. 

Key thoughts are now summarized in our whitepaper mini-series: ‘From academic concept to commercial reality: How to accelerate translational drug discovery’

In three chapters we share openly our insights and views to inspire a continued dialogue between academic researchers, investors, and biotech and pharma colleagues on how to build an even more robust translational community and – together, for medicines that matter - develop new first-in-class therapies and platforms.

Download the free content!

• INTRODUCTION
• CHAPTER 1
• CHAPTER 2
• CHAPTER 3
  
  

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Targeting RNA represents a paradigm shift for drug discovery. The ability to seek out and destroy, or modify, a faulty RNA template, before the toxic protein has even been made, has only recently begun to be harnessed for the benefit of patients. 
At the time of writing, 21 Oligonucleotide drugs have been approved for human use, with an exponential increase in clinical trials and development projects involving this new modality. 
There exist several different mechanisms of action for Oligonucleotide drugs, all of which are transient and reversible and do not lead to alteration of patient DNA, unlike Gene therapy. 

Antisense Oligonucleotides harness endogenous systems already existing within a cell to achieve their purpose, with the only limitation being accessibility of the target tissue.
Once bound with great specificity to its RNA target, a short synthetic Oligonucleotide can trigger degradation, upregulation of the translated protein, or alteration of a splicing event leading to a correctly folded protein. Longer Oligonucleotides can fold into 3 dimensional shapes called Aptamers with similar target affinities and applications as antibodies, and shorter Oligonucleotides can act as MicroRNA   mimetics or antagonists to alter multiple targets or pathways concurrently with subtle but broader effect. 

The precision of an Oligonucleotide and its ability to correct a faulty RNA produced by an error in the genetic code, lends itself to applications in the fields of rare disease therapeutics and toxic gain of function mutations. The field of Oligonucleotide therapeutics is developing to address this as a whole and to pioneer a new preclinical and regulatory path that could be adapted for these unique disease biologies to make this type of therapeutic innovation more accessible. 

Evotec is a leader in integrated end-to-end Research and Development and has built substantial drug discovery expertise and technical capabilities that can drive new innovative and diverse modalities into the clinic. In addition, Evotec has developed a deep internal knowledge base in key therapeutic areas including neuroscience, pain, immunology, respiratory, women’s health, aging, fibrosis, inflammation, oncology, metabolic and infectious diseases. Leveraging these skills and expertise, Evotec successfully delivers on superior science-driven discovery and development alliances with pharmaceutical and biotechnology companies.

The global interest in this new modality area has led to high demand in Oligonucleotide synthesis and related chemistry applications, from modified Oligonucleotides to conjugates and complex formulations. 
Evotec offers Oligonucleotide research and development capabilities as well as ligand and linker chemistry expertise to support projects from discovery through to development.

This fully integrated suite of capabilities allows for the synthesis, purification, isolation, and quality control of complex modified Oligonucleotides (ASOs, siRNAs, etc) on a scale from milligrams up to 25 g (up to 12 millimoles). The objective is to support Oligonucleotide drug discovery and development projects from the earliest phases of discovery, such as the generation of screening libraries, up to the selection of a preclinical development candidate followed by manufacture and release of material to support initial preclinical development studies. 

All these activities are supported by an experienced Oligonucleotide chemistry team operating across two sites and at different scales, to ensure flexible support for projects with highly efficient information and process transfer.
Evotec capabilities also include expert analysts for Analytical Development and QC, capable of developing and validating the analytical procedures needed for a full characterization and routine testing of Oligonucleotide drug substances up to and including IND enabling studies. In addition, Evotec’s support can encompass the release of preclinical batches according to regulatory requirements, including stability and formulation studies.

The journey to commercialization can be challenging. Scaling up production while maintaining process consistency, product quality, and regulatory compliance, requires expert process development capabilities, and the adoption of innovative science and risk management methodologies. A common pitfall for the Sponsor of an innovative therapy is to under-estimate the complexity and intricacy of this enterprise, which involves the coordinated optimization of strategies for process control, risk management, data management, and supply chain management.

With ever-evolving regulatory requirements and the increasing urge to shorten drug development timelines, getting your drug to market can seem like a daunting undertaking. That’s why taking some of the pressure off your organization by outsourcing your drug development and manufacturing activities to an expert partner can be the smartest decision. This will ensure your drug is commercialized in the fastest and most cost-efficient way possible, utilizing expertise, facilities, equipment, and processes to anticipate and overcome any challenges thrown at your program with ease.

Evotec offers an integrated end-to-end solution for innovative drug R&D, with the capabilities to support all phases of your drug development program. Your projects are in safe hands with our team of expert scientists who are pioneers in QbD, process design, scale-up, and validation, operating to full cGMP within FDA, MHRA, AIFA and BfArM approved facilities.

Our experts are just a click away! 

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Don’t miss our educational webinar series on “Oligonucleotides Therapeutics: Discovery to Development”

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