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 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.
Product development for a new viral vector-based product typically requires a custom-developed manufacturing process. In particular, scaling up viral vector production for clinical manufacturing requires specific know-how that can only be gained from years of experience in the field. For this reason, partnering with a CoE CDMO that specializes in viral vectors is often the wisest choice to de-risk and accelerate such programs.
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.
Developing a successful viral vaccine or viral vector for use in a clinical setting is notoriously challenging. Unforeseen pitfalls and roadblocks in process development and scale-up can lead to costly delays. Worse still, a poorly developed process can be difficult to control. This can adversely impact many factors, including production costs, yield, and even efficacy of the final product. Given the complexity, significant time investment, and high risk inherent in developing viral vaccines, viral vectors and other virus-based products such as oncolytic viruses and cell or gene therapies, outsourcing some or all of the development process is often a wise choice to de-risk your project, shorten the development cycle, and improve the final outcome. Is outsourcing right for your project? Here are some key considerations to help you decide.
CRO, CMO, CDMO – What’s the difference?
When it comes to outsourcing, there is often some confusion over which type of partner is most appropriate. While the answer depends on your specific needs, goals and in-house capabilities, there are 3 main outsourcing options:
Contract Research Organization (CRO) – A CRO facilitates the research and discovery phase of product development. This may be the right choice for companies looking for help with ideation and proof-of-concept, but a CRO typically will not have the dedicated resources and expertise to help with GMP scale-up for clinical trials and commercial manufacturing.
Contract Manufacturing Organization (CMO) – As the name suggests, a CMO focuses primarily on manufacturing, and is typically used later in development and for larger scale manufacturing projects. Many CMOs will have a fully developed and well-controlled process or platform for manufacturing, which they can adapt to fit incoming projects, but which may be less flexible in terms of development capabilities.
Contract Development Manufacturing Organization (CDMO) – A CDMO offers both development and manufacturing services, providing the expertise, support, equipment and facilities needed to take your process from proof-of-concept to clinical-scale production and beyond. This effectively bridges the gap between what CROs and CMOs can offer. Collaborating with a CDMO has the advantage that the people who develop your process will also implement it in GMP, eliminating the need for additional technology transfer.
Navigating the complexities of development and scale-up
Since process development is where many common pitfalls are encountered, a specialist CDMO is often the best choice for a start-up or small-to-medium enterprise looking to get a new vaccine, viral vector-based product or therapy to clinical trials as soon as possible, with the least amount of risk.
From definition of your process development strategy through to product release, there are countless scientific, technical, and operational aspects that need to be carefully planned, coordinated and controlled to ensure a successful outcome (Figure 1). This is where experience in process development will make a great difference—and consequently, it is often where collaboration with a CDMO can add the most value, compared to developing the process on your own.
Figure 1: Considerations in process development and optimization of viruses and viral vector-based products. (TPP: target product profile; QP: Qualified Person)
When deciding whether or not to outsource to a CDMO, here are some of the key development steps and related factors to consider:
Process development strategy. Planning is everything. As we touched on in the previous article, the myriad decisions you make at the start of your project lay the foundations for success—or failure. While this is true for any project, forward planning is especially critical in viral vector production due to the complexity of viral particles, the interdependencies of various processing steps, and the constraints imposed by GMP compliance. For businesses new to viral vector and viral vaccine production, or those seeking to accelerate development cost-efficiently, an experienced CDMO will be an invaluable resource. They will assess your current process, taking your target product profile (TPP) into account, and help you map out a plan to progress smoothly through the development process.
GMP compliance and regulatory. The manufacturer’s release of a biological product for its use in clinical trials is highly product-specific. It makes a big difference whether a monoclonal antibody or a viral vector has been manufactured. How much experience does your team have with developing a GMP-compliant process? Do you have an in-house expert with the requisite knowledge and awareness of regulatory requirements specific to viral vaccines and vector-based products? As you scale up production of viruses and virus-based products intended for clinical use, regulatory requirements become more stringent, and there are many different aspects that need to be considered to ensure the final process will be compatible with GMP manufacturing. As we saw in the previous article, failure to account for later stage regulatory requirements in the early development phases is a common source of project delays and failures. For example, it is not uncommon for clients to be unaware of, or unable to document, the origin of the cell line used for proof-of-concept studies, yet this knowledge is essential for a GMP compliant process. A specialized CDMO can spot potential GMP compliance issues like this before they become problematic, and ensure that your entire process is designed for compliance from the start.
Culture system definition and optimization. Regardless of your application, the production cell line and viral seed you are working with not only need to be GMP compliant, they also need to be productive, genetically stable, and robust to various upstream and downstream processing steps. A CDMO specialized in development and production of viral vaccines, viral vectors and other virus-derived products has experience with optimal growth of the mammalian cell types commonly used for manufacturing, such as Vero (for viruses such as measles, polio and VSV) and HEK293 (for viruses such as AAV, adeno and lenti). Moreover, they may be able to recommend and help you access cell variants that have been genetically engineered or further optimized for stability and high yield of viral particles. If needed, they may also be able to engineer the viral genome to tailor it to your requirements—for example, to ensure high expression of genes of interest. Once the culture system has been chosen, they can kickstart the development process with pre-developed SOPs and tailor them to the specific requirements of your target product.
Scaling adherent cultures.Scale-up of adherent cell cultures is a key undertaking where a CDMO’s input can significantly reduce risk and development time. In the vast majority of cases, viral vectors and other virus-based technologies are initially developed in an adherent cell line, and typically these cells are propagated in T-flasks or roller bottles. While this provides a convenient and familiar format for research and pre-clinical studies, it is generally not compatible with large-scale production. Is a fixed-bed bioreactor the way forward? If so, which type is most appropriate? Would 3D culture on microcarriers or switching to a suspension cell type give better results? A CDMO can help guide you through this decision process quickly, and then implement and optimize the solution as efficiently as possible. They are likely to have the equipment and facilities needed for scaled-down design optimization and scaled-up production, as well as having familiarity with cutting edge technological advances, such as new types of bioreactors, biomimetic and temperature-responsive growth substrates, and much more.
Recovery and purification. The characteristics and performance of viruses can be highly sensitive to process changes. Just as scale-up of upstream bioprocessing requires careful planning and consideration, so do the solutions implemented downstream. Conventional lab-scale methods such as cell lysis by freeze-thawing and ultracentrifugation for purification become impractical and costly at larger scales. Recovery and purification steps need to be appropriate to produce the amount of material needed at each phase, and upfront design is essential to avoid process changes later on that could potentially alter the properties of the product or the purification yields. Can your process be appropriately scaled-down for screening and optimization DoE (Design of Experiments)? Is your virus compatible with a final sterile purification step, or will you need an aseptic process? Which chromatography technology is right for your specific vector? Anticipating and effectively addressing critical questions like these requires years of experience and expert process knowledge.
Getting it right from the start
In this article, we have highlighted just a few of the many challenges and decision points that need to be tackled during development of viral vaccines, viral vectors and other virus-based products, such as oncolytic viruses and targeted cell or gene therapies. While CDMOs vary considerably in terms of their areas of specialization, as well as the breadth and depth of their offering, with the right outsourcing partner, it is possible to bypass many development risks and fast-track your product through the development process.
In 2017, the New York Times wrote an article to report the critical shortage in the global viral vector manufacturing capacity. Next to the shortage of experienced manufacturing organizations capable of producing viral vectors, the high costs to produce this material is a main challenge for patients awaiting a viral vector treatment. Novartis was the first company to market a viral vector-based gene therapy. They charge $475.000 for a one-time treatment per patient. Given the production issues, we expect that novel gene therapy products will be launched at comparable market prices. The production costs are high due to:
the high dose needed for the treatment of a patient
the low viral vector production yields obtained in current manufacturing campaigns
Therefore, there is an urgent demand to scale-up the manufacturing. This way sufficient product for the patients in a phase 1 clinical study can be produced. Additionally, we need a breakthrough innovation to improve the viral vector yield in current production processes. The yield is a major factor for the high cost of goods. A recent development which promises higher vector yields, is the rise of novel fixed-bed bioreactors. Herewith, I would like to guide you through some of my team’s experiences with this equipment for virus manufacturing.
The challenge for viral vector production
Most protein-based biopharmaceuticals are produced using suspension mammalian cell cultures. In contrast, most viral vectors are produced using adherent cells. Adherent cells will only proliferate and produce the desired product when attached to a surface. Therefore, traditionally static systems, such as T-flasks, Cell Stacks, Roller Bottles, or Cell Factories, were used. Unfortunately, such systems are very labor intensive, require a large footprint, and only allow very limited in-process control. The biggest issue, however, is the fact that these systems only allow increased production capacity through out-scaling instead of up-scaling.
The first scale-up alternative was the microcarrier system. In the 1970’s, van Wezel et al. developed this technology. The advantage of this system is that cells are grown on beads. These beads are suspended in a tank and agitated, providing a homogeneous environment and the possibility to scale-up. Therefore, this technology provides similar characteristics to suspension cells. Nowadays, several viral vaccines are produced using a microcarrier system. There are, however, a few downsides to this system. Expert know-how and experience is absolutely required to avoid reduced cell growth. This is particularly true for production at larger scales. Reduced cell growth has been a common observation in microcarrier-based processes because of the agitation needed to keep the microcarriers in suspension. In addition, separating the virus product from the microcariers upon harvest requires an extra step. Each extra step has the potential to reduce the overall yield of the viral product.
Fixed-bed bioreactors for viral vectors
The second scale-up alternative is the use of fixed-bed bioreactors. Fixed-bed bioreactors are two-phase systems in which the medium flows continuously through a stationary bed made of a porous polymer. Because the matrix on which the cells are growing is fixed, the cells have to endure substantially less shear stress, while process parameters such as pH and dissolved oxygen can still be tightly controlled. This set-up generally allows for high cell densities in a small-footprint bioreactor and easy recovery of the viral vector product.
Our process development data
My team at Batavia uses both the scale-X™ and iCELLis® fixed-bed bioreactors. We gathered a wealth of data on both systems. For example, the scale-X bioreactors have been successfully used for the Sabin poliovirus strains (PV1, PV2, PV3) production. As a direct comparison of our results in the scale-X bioreactor with the microcarrier production process described in literature, an average yield increase of 178% (in DU/cm2) was achieved for the 3 serotypes of poliovirus.3 In addition, the scale-X bioreactor was implemented for production of the VSV vector in our Lassa and Marburg vaccine programs.
Using iCELLis® bioreactors, lentiviral vectors have been successfully produced in our lab. We corroborate the conclusions of Valkema et al. that iCELLis® bioreactor based processes are much easier to be scaled up and use significantly less floorspace compared to the T-flask based production process.
Overall, our working experience with fixed-bed bioreactors is very positive, because it provides smooth scale-up, is less labor intensive, and we are able to reach very high cell densities. These high cell densities benefit transfection efficiency and product yield. We therefore believe that these systems may substantially contribute in overcoming viral vector manufacturing cost.
Batavia Biosciences offers a broad range of process development and manufacturing services for all major classes of biopharmaceuticals. We are dedicated to help bring biopharmaceuticals to the market at higher speed, with reduced costs, and with a higher success rate. Batavia Biosciences has vast experience in developing and manufacturing vector vaccines, gene therapy vectors and oncolytic vectors. Our team of experienced scientists and technicians are well equipped to take on any challenge associated with viral vector development.
With the first gene therapies now being on the market, the production quantities for gene therapy vectors are increasing to satisfy the demand. A steady increase of product titers and the corresponding change in impurity composition represent a challenge for development and optimization of viral vector production processes. The availability of purification processes, or downstream processes (DSP), capable of handling these increasing quantities and concentrations are becoming a bottleneck for many manufacturing processes. The DSP should deliver viral vectors with levels of purity and biological activity at par with regulatory standards. It should be irrespective of the permeations inherent in any USP process.
Advancements in downstream processing of viral vectors
Viruses far exceed the dimension of proteins used in pharmaceutical applications with respect to weight and size. Therefore, purification of viruses is more complex than simply ‘plugging’ viruses into existing protein purification schemes. This will not yield adequate results. For example, in chromatography the traditional bead chromatography methods are not ideally suited for most viruses; due to the size of viruses, which diffuse much more slowly compared to proteins. Additionally, viruses may be excluded or be entrapped in the chromatographic bead pores. These pores normally contain the majority of binding sites. Also, viruses, being complex macromolecular assemblies, have significantly lower titers compared to proteins. Therefore, the ability to handle large volumes is also beneficial and is limited in traditional beads.
More recent innovations, such as membranes and monoliths are much more suitable for viral applications. This is, for example, due to their accessible binding sites and large pore sizes. Moreover, they do not rely on diffusive transport. Membranes and monoliths also have benefits in containment, because they can be single-use and pre-packed, while traditional columns are often packed by the operator. Other benefits of the non-traditional methods over the use of beads are lower buffer consumption, due to the relatively small bed volume and lower process times, owing to the high flow rates that can be employed. The only downside of membranes is a lower resolution, but for many virus-based products a high resolution is not required.
Future needs in DSP
These non-traditional chromatography methods are already able to tackle part of the DSP capacity bottleneck, but at Batavia my team and I are working on new innovations to meet future requirements and cope with the increases in USP productivity and market requirements.
We are dedicated to help bring biopharmaceuticals to the market at higher speed, with reduced costs, and with a higher success rate. Batavia Biosciences has vast experience in producing and purifying viral vectors. Our experienced DSP-experts are well equipped to take on any challenge associated with purification of biopharmaceuticals.
