Batavia Biosciences announced significant progress in expanding its biomanufacturing facilities in Leiden, the Netherlands. Just two months after the first pile was drilled, Batavia continues to expedite this flagship project in conjunction with VILS and Provast.
VILS, a subsidiary of XILS and part of the Masco Group, and the real estate developer Provast, have been awarded the RTB – “Ready to Build” design. This noteworthy milestone follows the creation of the GMP Part’s concept design and the premises’ supporting functions.
The GMP-scope design is based on a hybrid delivery model that combines offsite modular prefabrication to expedite critical construction elements with stick-built methods for less time-critical sections. This strategic model accelerates the project while maintaining meticulous attention to detail.
Under the contract, VILS, in conjunction with its sister company BILS, will elaborate on the final design to allow BILS to provide Batavia with a detailed quote for the turnkey execution of the technical fit-out. This will include advanced labs and cleanrooms to facilitate cutting-edge biomanufacturing.
Ief Leroy, CEO of XILS, expressed his enthusiasm, stating, “We congratulate Batavia on this critical next step. We are delighted by their strong commitment and trust in our abilities to deliver this time-critical and complex project.”
Eize De Boer, MD of Batavia Biomanufacturing, added, “We are pleased that VILS & BILS were able to provide us with an Integrated Project Delivery solution for our project. This streamlined approach consolidates management and responsibilities, enhancing efficiency and ensuring a clear line of accountability.”
Frans K.A. Maas, Board member of XILS and Masco Group, further reinforced this sentiment, “With the integrated solution co-developed by VILS and our Masco sister-company KeyPlants, we can offer a comprehensive solution that provides significant time savings for all parties involved.”
They are thought leaders and experts in Integrated Project Delivery for Capital Projects for Cell and Gene therapies and Cellular Agriculture.
About Batavia Biosciences/Biomanufacturing
Batavia Biosciences is a renowned CDMO and a strategic thought partner, offering bespoke services from development to GMP manufacturing for viral vectors, viral vaccines, and recombinant proteins. With plans to expand into commercial manufacturing, our unique approach and presence in the EU and the US enable us to significantly contribute towards alleviating human suffering from infectious disease and cancer.
Welcome to the next chapter in the evolution of biomanufacturing!
On behalf of Provast and Batavia Biomanufacturing, we invite you to join us for the groundbreaking event on May 11, 2023. This momentous occasion marks the dawn of a new era in our history, as we embark on a journey to revolutionize the biomanufacturing industry.
At this landmark event, you’ll have the opportunity to:
Witness the groundbreaking ceremony
Discover our vision and strategic plans for the future
Networking with peers over drinks and a bite
Don’t miss this opportunity to be a part of Batavia Biomanufacturing’s future and join us in shaping the landscape of biomanufacturing for years to come. Secure your spot now and experience firsthand the excitement and potential of Batavia Biomanufacturing.
15:45 – Walk-In 16.10 – Welcome by Hans de Jong, Partner of Provast 16.15 – Welcome by Eize de Boer, General Manager Batavia Biomanufacturing 16:20 – Batavia Time Capsule 16.25 – Groundbreaking ceremony with Wethouder Fleur Spijker 16:30 -Drinks & Snacks 18:00 – Event Conclusion
Please note: Attendance for this event is limited, so be sure to reserve your spot today. Simply click complete the registration form to secure your spot.
You’ve developed a candidate viral vaccine or viral vector product, and initial preclinical data are showing excellent efficacy. Now you’re ready to scale up for IND application and testing in human subjects…or are you?
Whether you are developing a viral vaccine, cancer vaccine, oncolytic virus, gene therapy or other viral vector application, the choices you make at this critical stage can greatly influence the success or failure of your project. In this article, we explore common pain points and some of the most dangerous pitfalls that process development teams encounter when scaling viral vector and vaccine production for clinical trials and beyond.
Viral Vaccine and Viral Vector Manufacturing: The High Price of Failure
The viral vaccine and viral vector industry is notoriously challenging, with long candidate development times and high attrition rates. Compared to traditional pharmaceuticals and recombinant protein therapeutics, the added complexity of viral biology compounds the difficulty of developing a well-characterized and robust manufacturing process.
Historically, developing and licensing a vaccine takes from 10-14 years, with only 6% of candidates progressing from the preclinical phase to market [1-3]. Given that the average cost of moving a single vaccine candidate through to the end of phase 2a clinical trials is between $31m and $68m, the price of failure is high . In many cases, the underlying causes of this high attrition can be traced directly or indirectly to decisions made in the early development phases.
Dialing up production from lab-scale to clinical trial levels may seem like a straightforward exercise, but in reality the process can be complex, time-consuming, and expensive. Unexpected problems introduced by poor design choices, process changes, and unpredictable biology can seriously delay your project or derail it altogether.
So, what’s the good news? With careful planning, informed choices, and intelligent design from the very beginning, you can de-risk your project and possibly even accelerate it in the process. But before we get into that, let’s dig a little deeper into why development and scale-up of these types of products are so risky.
Why is Scale-Up of Viral Vectors So Challenging?
Biological entities like viruses are inherently complex and difficult to control. Rather than consisting of a single, well-defined chemical or biomolecule, viral particles are relatively large multi-component structures. This means that compared to other therapeutics like recombinant proteins, for example, the production process is often more complicated, and there are many more elements that need to be characterized, optimized, and controlled to ensure the structural and functional integrity of the final product.
During upstream processing (USP) for viral vector products, the vector, production cell line, and culture system together comprise an even more complex system, with many interdependencies that need to be considered holistically. In order to optimize for safety and productivity, as well as to ensure that critical parameters are maintained during scale-up and clinical production, this whole system needs to be thoroughly studied and understood.
Any changes to viral seeds or cell banks, raw materials, culture parameters or other upstream processing steps can have a profound impact on the downstream process. It’s therefore essential to develop a robust model of your process, so that you can optimize and scale-up your process in a controlled manner.
5 Scale-Up Pitfalls For Viral Vector Manufacturing
The transition from the initial lab-scale process to a final commercial process needs to be planned carefully from the beginning to avoid surprises later on, after significantly more time and money has been invested in development.
With this in mind, here are some of the most dangerous rocks to avoid as you navigate the treacherous waters of viral particle scale-up:
Insufficient System or Process Knowledge
After years of painstaking research and successful completion of proof-of-concept studies, it might seem reasonable to assume that you already know everything you need to know about your product, and the process you have designed may have worked well to support preclinical animal studies.
However, as you progress to human clinical trials, and later into commercial production, your vector will need to be manufactured at scales that are multiple orders of magnitude larger than those required for animal studies. At these scales, the influence of variables that were paid only limited attention during preclinical investigations often becomes more apparent. For example, slight variations in the timings of infection or harvest could lead to varying levels of inhibitory metabolites in the culture medium, which in turn limit your potential to achieve the best possible yields or virus quality at production scale. If these metabolites have not previously been profiled, this could cause an unexpected development bottleneck.
As this scenario illustrates, without sufficient knowledge of all the relevant process parameters and their interactions, development complications and delays are almost unavoidable. It can be virtually impossible to keep your process under control, predict how process changes will affect the product CQAs (critical quality attributes), and optimize for factors such as cost-efficiency, performance and yield.
Many critical performance indicators and interdependencies are not obvious, and don’t become apparent until you deliberately go looking for them in a systematic way, by applying quality by design (QbD) principles throughout the whole development phase.
Putting Too Much Faith in “Plug & Play” Manufacturing Platforms
A recent and highly enabling trend in the viral vector market is the use of platform manufacturing processes to simplify and accelerate the development process—particularly when generating material for phase I clinical trials. Such platforms use prefabricated processes (USP, DSP and non-product specific assays) that have previously been developed for a particular vector backbone. Instead of developing the process from scratch, your vector backbone is simply plugged into a platform process that has been designed for a similar vector. The majority of effort can then be focused on confirming that the process yields material of sufficient quantity and quality for phase I testing.
In many cases, a platform process can cut development time down by several weeks or even months, and is the best option to reach the phase I milestone as quickly as possible. Nevertheless, it is important to recognize that the platform approach is no substitute for true process development capabilities and expertise.
Given the inherent complexity of viral vectors and the current state of the art when it comes to standardization of platform technologies, there remains a very real chance that a particular platform will be unsuitable for your viral vector. In this case, it is vital to have the necessary process development capability on hand to keep your project back on track. Even in cases where the platform approach does prove successful, further process development is always needed in order to progress to phase II studies. This means that if either you or your development partner lacks the requisite capabilities in-house, valuable time can be wasted and additional costs incurred to transfer the technology to a partner with the right process development and manufacturing capabilities. At minimum, your new partner will need to carry out a process confirmation run, as well as additional work to implement and qualify the necessary analytical assays.
Failure to Design For Scalability
Designing for scalability goes hand-in-hand with modern QbD strategies. Since process scale-up can lead to many unexpected problems and bottlenecks in development, it’s important to design your process with the end goal in mind. While this concept may seem obvious, the importance of designing for scalability is often underappreciated. The final scale requirements impose various constraints and have far ranging effects on many factors, such as choice of equipment, cell line requirements, raw materials, cost of goods (COG), and even end-product formulation and stability.
Skipping or postponing steps in the development process may sometimes seem expedient, but in the long run they can cause more problems than they solve. For example, the majority of viral vector processes are initially developed in adherent cell cultures that are propagated in T-flasks. In such cases, the quickest way to produce enough material for phase I trials may be to take the traditional approach of expanding the surface area and number of flasks (scale-out), rather than going down the more time-consuming route of transitioning to a fixed-bed bioreactor or microcarrier culture system (scale-up).
While this shortcut may get you to clinical trials faster, ultimately this approach is more costly, difficult to control, labor-intensive, and takes up more lab space. Switching to a bioreactor format, such as a fixed-bed or microcarrier format, could help overcome these problems. However, if you do this at a later phase in development, it is a process change that can potentially lead to unpredictable changes in the product CQAs. As a result, additional studies will be necessary to demonstrate comparability of product efficacy and safety.
Similarly, it may be tempting to postpone in-depth product characterization until the later stages of development. However, if this can be achieved using material produced under scaled-down conditions that adequately mimic the final process, you will have more time to de-risk your process and identify the most cost-efficient solutions.
GMP compliance expectations become increasingly stringent across the product development stages. No matter how carefully you plan, process changes may be needed during clinical development scale-up and optimization. These changes will have regulatory implications that you need to bear in mind.
When planning to launch in different regions, it’s also important to be aware of any differences in local regulatory requirements and guidance that could affect your product or process design. In addition, documentation and process materials that worked at research stage may no longer be adequate to ensure compliance. In a nutshell, regulatory awareness and design for cGMP compliance is essential for success, and should be accounted for as early as possible in the development process.
From Problems to Solutions
In this article, we’ve touched on some of the biggest sources of project delays and failures in viral vaccine and viral vector production, but there’s a lot more to learn, and of course it’s not all doom and gloom. In upcoming articles, we’ll turn our attention to the practical steps and considerations that will help you bypass these problems and get your product to market sooner.
When it comes to outsourcing, there is often confusion about the type of partner that is most appropriate for a project. In our previous article, we discussed the difference between a CRO, CMO and CDMO. In this article, we would like to zoom in on the different type of CDMOs in the field of biopharmaceutical contracting.
Different types of CDMOs
The term CDMO is becoming fashionable. More and more CMOs are adding the D for development to highlight that they have more to offer than manufacturing biopharmaceuticals. However, there is a great variety in CDMOs in terms of capabilities and expertise. For example, many of the large CDMOs apply a business model focused at late-stage and commercial manufacturing.
As a result, larger CDMOs tend to offer process development services only to those companies who are willing to sign for late-stage manufacturing, which is where most of their profit is generated. On the other hand, there are CDMOs whose primary focus is on process development rather than manufacturing. They perform GMP manufacturing only for the processes they have developed and know better than anyone.
The most notable difference in CDMOs is that between what we call a ‘vendor CDMO’ and a ‘Center of Excellence (CoE) CDMO’.
Vendor CDMOs focus on operational excellence, meaning they’ve optimized one or more standardized processes and, as a result, are able to keep the prices for their services below market average. These companies must apply economies of scale to keep their costs and, subsequently, their prices low. This requires heavy spending on facilities and equipment to achieve efficiencies.
Projects that are an excellent fit for vendor CDMOs are those that fit their standard processes. Typically, these projects are strongly defined by nature, and commodity based. The production of a master cell bank is an example of such a project. In general, making a cell bank is very straightforward. Outsourcing such a program to a vendor CDMO is an outstanding way to cut expenses, without too much risk.
Vendor CDMOs are able to handle large volumes of such projects, because they have optimized every step of the process. Their staff is trained to repeat the same step over and over again very accurately. But what if your program doesn’t fit the platforms of these CDMOs?
Center of Excellence CDMO
When you have a unique project, requiring a company to provide knowledge to make it a success, a CoE type of CDMO would be a better fit for you. CoE CDMOs provide leadership in a certain focus area, share best practices, perform research, and provide support. Many CoE CDMOs offer consultancy services next to their process development and manufacturing capabilities.
The business model of a CoE is based on creating long-term partnerships with their customers, to whom they offer tailored services. Because this model requires hiring a highly educated and experienced staff, requires a higher level of customer intimacy, and attracts more high-risk projects, prices tend to be above the market average. In return, the customer can expect a higher level of quality, flexibility and customer service than a vendor CDMO could provide.
Batavia Biosciences is a Center of Excellence for viral vaccine and viral vector development with extensive experience in the field of infectious diseases and oncology. Interested to learn more about what we can do to help your product development moving forward?
The Netherlands has a long history in the life sciences industry. Especially in the field of vaccine development and manufacturing, this small country has always played a significant role. Lately, the rich history proved a fertile ground for developing and manufacturing a wide variety of SARS-CoV-2 vaccines.
The website Invest in Holland has written an interesting article on how the Dutch became such a prominent player for vaccine development. Gerard Schouw, Director of the Association Innovative Medicines, states in the article:
“The Dutch life sciences & health sector has been at the innovative forefront of Europe for many years. The Netherlands has a lot to offer due to its central location in Europe and successful history of public-private partnerships.”
Role of Batavia in vaccine development
We, at Batavia, are proud to play our part in the development of new and innovative vaccines. In the recent years, we have announced partnerships for the development of vaccines against viruses like: SARS-CoV-2, polio, Marburg, Lassa, rota, measles, and rubella.
In each project, we strive to improve the affordability and availability of these life-saving medical countermeasures. For example, with our HIP-Vax® platform for low-cost, highly intensified manufacturing, we are able to bring the Cost of Goods of vaccine manufacturing well below <$1.00 per dose and reduce the time from bench to clinic to 9 months. This timeline is including the biosafety testing. These benefits are the result of significant reductions in the manufacturing footprint, increased cell density and less process steps.
With our extensive bioprocessing knowhow, we will continue to expand our footprint in the vaccine development sector until all those in need have access to vaccines.
Over the last decade, the scientific community has witnessed several breakthroughs in the field of gene therapy and immuno-oncology. These breakthroughs have propelled the interest in the development of Advanced Therapy Medicinal Products (ATMPs), i.e., medicinal products for human use, based on genes, tissues or cells (see figure 1). Such products currently offer hope in the treatment of genetic disorders and cancer where previously there was none.
Fig. 1 Market development of viral vector therapies
Many ATMPs under development rely on the delivery of genetic material to cells of a patient using so-called viral vectors. Viral vectors are usually derived from parental wild type viruses whose viral genes (essential for replication and virulence) have been replaced with the heterologous genes intended for cell manipulation. In vitro and clinical use of viral vectors is based on RNA and DNA viruses that differ in their genomic structures and host range. Specific viruses have been picked as gene delivery vehicles according to their capacity to carry foreign genes, as well as their ability to conveniently deliver genes that are linked to efficient gene expression.
Here, we address some of the challenges in viral vector manufacturing that manufacturers are tackling, specifically to the production of viral vector based ATMPs. Although we focus on two viral vectors, i.e., adeno-associated virus (AAV) and lentivirus derived vectors as these two systems are mostly selected for the development of ATMPs (see figure 2), most vector systems under development face similar challenges.
Figure 2: Distribution of gene based ATMPs in development based on platform.
In a nutshell, the challenges in manufacturing AAV and lentiviral vectors are across the board meaning that production, purification, and product quality is up for improvement. In production, it’s the viral vector titer that needs to be drastically increased, in purification recovery of product needs to be drastically improved, while ensuring other critical quality attributes (such as the transducing titer for lentiviruses or the number of empty particles when working with AAV) are not affected. Substantial improvements in all fields are deemed essential to reduce cost of goods, increase manufacturing success by limiting batch-batch inconsistencies, and lower the therapeutic dose to improve product safety profile.
How Batavia is hurdling the obstacles of viral vector production
To start tackling these issues, industry is turning its focus on the development of automation and the development of Process Analytical Tools. Recent advances using DOE approaches to optimize the cell culture and transfection processes have been described as well as the development of specific technologies to increase downstream recovery. In addition, an exciting new prospect is provided by the generation of stable vector producer cell lines, capable of expressing complete viral vector particles upon induction. This technology delivers higher titers and, so far, seems to deliver more consistent product quality compared to transfection processes.
At Batavia, we focus on scalability of viral vector manufacturing processes, using our HIP-Vax® platform. This platform uses fixed-bed bioreactors and is based on the principles of process intensification. In the field of monoclonal antibody production, process intensification has already been adopted as one of the key manufacturing strategies to realize low cost of goods. Now it’s time to do the same for viral vector products.
Due to the high productivity of this production platform, it requires only limited sized clean rooms, making this manufacturing platform well suitable to produce viral vectors for ex vivo therapies for which only small volumes are required for individual patient treatment protocols. However, the technology also provides a vector yield output at approximately 50-liter scale equivalent to a 1000-liter suspension reactor owing to the high cell density culture.
This advantage of the HIP-Vax manufacturing platform, i.e., the ability to manufacture product at a small facility footprint has been amply demonstrated to substantially lower the costs-of-goods of the production process, due to the increase in batch output, and a decrease of costs associated with raw materials.
Our HIP-Vax platform modernizes viral vector production by increasing both yield and improving product quality. Additionally, owing to its low footprint, it helps solve the current capacity constraints in the viral vector industry.