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Through the use of liquid handling automation and high resolution mass spectrometry, high quality data is delivered rapidly to feed into drug discovery programs.
Tags: Fact Sheets, ADME/DMPK
Tags: Drug Development, Infographics
Over the past two decades, biotherapeutics, particularly monoclonal antibodies (mAbs), have transformed the therapeutic landscape for a range of prevalent health conditions, from autoimmune diseases to cancers. It’s also been estimated that some 7,000 rare disease indications could be addressed with biotherapeutics (1). However, while biologics have shown remarkable efficacy in clinical settings, access to these therapies remains a significant challenge globally.
Most biologics developers rely on fed-batch systems for bioproduction. However, this approach brings several key challenges that create risks and inefficiencies in the production pipeline, including:
In this blog, we’ll explore these major factors influencing the supply and access of commercial biologics, before highlighting how adopting a continuous manufacturing approach can address these challenges.
Fed-batch manufacturing involves discrete unit operations where production occurs in separate, sequential steps. Each step must be completed before the next one begins. This means large volumes of intermediates must be stored, which requires a substantial facility footprint.
Running these large-scale facilities is expensive and contributes to the high costs of manufacturing. Additionally, fed-batch processes often require significant manual input, needing large teams of operators for their execution, increasing costs further. As a result, fed-batch facilities run at a higher operational cost compared with continuous bioprocessing units.
It’s challenging for biologics developers to accurately predict the take-up and global demand for a biologic, especially during early production phases. If demand is too low, it can lead to sponsors paying out for idle manufacturing capacity. Should demand be higher than forecasted, sponsors run the risk of underproduction, causing shortages and patients going without medicines.
Further adding to this problem, fed-batch processes rely on large-scale stainless-steel units for commercial supply that are expensive and time-consuming to build. This creates inflexibility, bringing difficulties in adapting fed-batch units to fluctuating demands. This scenario was experienced by the developers of rheumatoid arthritis therapy Enbrel®. During times of increased demand, such as when new indications were approved or patient populations grew, inability to rapidly scale up production of their fed-batch process caused serious supply constraints (2).
Fed-batch biomanufacturing processes face significant risk when it comes to scaling up production, especially for sponsors moving from clinical trials to commercialization. This can limit the ability of manufacturers to meet global demand.
Fed-batch processes must be scaled up by a factor of 5 to 20-fold in order to meet commercial demand, because of the inefficiency of the process.
Scaling up in this way creates the following risks:
Biologics provide life-saving treatments, but access and supply have been limited due to their high cost structure, inflexible production processes, and unpredictable demand. Continuous manufacturing addresses these challenges by offering a more agile, cost-effective, and stable production process.
This approach involves raw materials being continuously fed into the bioprocessing system, while products are continuously yielded. By automating workflows and maintaining a steady state of operation, companies can improve scalability, adaptability, productivity, and consistency. Companies that have started their clinical journey with a fed-batch process should consider converting to a continuous manufacturing platform before commercialization to take advantage of these benefits.
Learn how continuous manufacturing can slash biologics production costs by 75 %
To maximize manufacturing outcomes, opt for an industry-leading partner like Just – Evotec Biologics. Partners can benefit from cutting-edge continuous manufacturing technologies, well-established process development systems, and state of the art J.POD facilities.
1. Chediak L. I have a rare disease. This is my hope for the future of medicine. World Economic Forum.
2. Gellene D. Immunex says Enbrel shortage worse than anticipated. Los Angeles Times.
Tags: Formulation & CMC, Biologics, Immunology & Inflammation, Clinical Development
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.
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.
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)
Tags: Oncology, Blog, Biologics, Immunology & Inflammation, Rare Diseases, Clinical Development
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!
Visit our Academic BRIDGEs website page
Discuss your project with us:
Tags: Drug Development, Drug Discovery, BRIDGE, Articles & Whitepapers, Blog
Just- Evotec Biologics is pioneering a new era in biomanufacturing. Transitioning to our intensified continuous production before manufacturing at commercial scale can drive value creation in a late-stage manufacturing process. Additionally, as we offer a short feasibility study, this is a low-risk method for evaluating the benefits our workflow can bring, without impeding development timelines.
Tags: Oncology, Articles & Whitepapers, Formulation & CMC, Biologics, Immunology & Inflammation
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!
Don’t miss our educational webinar series on “Oligonucleotides Therapeutics: Discovery to Development”
Tags: Drug Discovery, Medicinal Chemistry, Blog, Formulation & CMC, Hit & Target ID/Validation, In vitro Biology, IND Enabling Studies/Preclinical Development, oligonucleotides
The long-awaited ICH M12 harmonised guideline on drug interaction studies was adopted on 21st May 2024. It is just a matter of time before it is implemented by the main regulatory agencies – in fact, the European Medicines Agency has already reached Step 5 of the process and announced that the guideline will come into effect on 30th November 2024. Therefore, it is essential companies are prepared for the change and know how the ICH M12 guideline differs from earlier guidance/guidelines so data can be collected and analysed correctly according to the new recommendations.
Cyprotex has produced some easy-to-follow flyers which highlight the key differences between existing guidance/guidelines from the US FDA, European Medicines Agency (EMA) and Japanese PMDA and the new harmonised ICH M12 guideline. These will help you get started on the transition process.
European Medicines Agency (EMA) vs ICH M12 Flyer
Japanese PMDA vs ICH M12 Flyer
Cyprotex is a centre of excellence for drug-drug interaction (DDI) studies. Our highly experienced team provide consultancy and guidance, and support you with the design, implementation and interpretation of in vitro DDI studies according to the regulatory guidance/guidelines, including the new ICH M12 guideline.
Discuss your project with us:
Tags: Blog, ADME/DMPK, IND Enabling Studies/Preclinical Development
With high attrition rates of mAbs in early phase clinical trials, it is becoming increasingly challenging for biopharmaceutical companies to rapidly deliver high quality therapeutic mAbs using conventional antibody screening and fed-batch bioprocessing methods. This is why new Quality by Design (QbD) approaches such as using in silico AI and ML platforms to discover and optimize mAb sequences, high-throughput screening, and continuous intensified manufacturing processes such as those used at Just- Evotec Biologics are critical for enabling a paradigm shift in reducing attrition rates.
As detailed in this article, optimizing mAb design, using automated, miniaturized screening, and minimizing time in culture can deliver high-quality mAbs for FIH trials in rapid response times of around 12 months. In the future using this approach could expand access to life changing treatments, as well as support a rapid response to global health emergencies.
Tags: Articles & Whitepapers, Formulation & CMC, Biologics, Clinical Development
