Accelerating Viral Vector and Vaccine Development: Beware Of The Pitfalls of Scale-Up

Accelerating Viral Vector and Vaccine Development: Beware Of The Pitfalls of Scale-Up

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 [4]. 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.

Shortcuts

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.

Regulatory Snags

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.

Adenovirus Vectors in Gene Therapy – Vaccine Development & Delivery Tools

Adenovirus Vectors in Gene Therapy – Vaccine Development & Delivery Tools

Adenovirus Vectors in Gene Therapy – Vaccine Development & Delivery Tools

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Adenovirus  vectors are a form of viral vectors which are used to develop gene therapy products and vaccines. Decades of research stand behind these vectors which have gone through several iterations and improvements to make them what they are now.

A History of Adenovirus Vectors

As mentioned in a previous article, the E1 proteins which control the adenoviral replication cycle were removed in very early iterations of the adenovirus vectors. This prevented the virus from replicating in humans, thus only allowing the virus to deliver its genetic payload. In addition, the E3 region, which is not essential for viral propagation, was removed. The space freed up in the wildtype virus genome by the removal of E1 and E3 allowed for the insertion of up to 6.5 kb of foreign DNA.

This was the first generation of adenovirus vectors.

In the second generation more improvements were made when E2a, E2b and E4 were removed. The removal freed up yet more space in the genome for up to 10.5 kb of transgene DNA to be inserted into the chromosome. This was particularly relevant for researchers desiring to put multiple antigens into one vector. For instance, in pursuit of AIDS vaccines it was shown that a combination of HIV virus-derived envelope together with Gag and Pol provided broad immune responses. The deletion of more genes encoding for E proteins from the viral backbone also improved the safety of Ad vectors by making it less likely that spontaneous recombination events during the vector propagations would lead to replication-competent viral particles. The deletion of multiple E-encoding genes from the viral genome also led to a significant reduction in viral gene expression in host cells, lowering a cytotoxic T-lymphocyte response against the vector itself. This made second generation Ad vectors much less likely to be cleared by the immune system.

Third generation Ad vectors are void of all viral sequences except for the inverted terminal repeats, which are the signals for the DNA to be effectively packaged into the adenoviral capsid proteins. These high-capacity adenovirus vectors can package up to 36 kb of foreign genetic material. To produce these vectors, adenoviral helper viruses are required to produce the proteins needed for replication and packaging of the Ad vector genome.

Recombinant Ad vectors have been around for a long time and the active research around them has led to great leaps forward in their usage and in the fields of gene therapy and viral vaccine production. Currently, it is possible to make conditionally replicating Ad vectors, which only replicate inside tumor cells. When this is combined with the effective cell targeting provided by transgenic knob proteins on the capsid surface, Ad vectors become a truly powerful tool for cancer therapies as well.

Main Advantages for Adenovirus Vectors

Ad vectors have advanced further than any other vector system owing to continued active research from academia and industry together. This research has made Ad vectors more effective while also making them safe. Modern Ad vectors have four key advantages in gene therapy and vaccine development.

1. High Transduction Efficiency in Dividing and Quiescent Cells

This is one of the reasons that adenoviruses were first considered as vectors for gene therapy and vaccines. Ad vectors can deliver genetic cargo to cells very efficiently, so that therapeutic levels can be achieved with fewer viral particles. This is extremely important for in vivo systemic applications where high concentrations of Ad vector are typically more challenging.

2. Epichromosomal Persistence in Cells

This feature of Ad vector has led to some very specific and highly sought-after applications. Persistence of the vector is important to allow the genetic payload to be delivered, transcribed, and expressed as therapeutic proteins. Without the ability to persist, these therapies would not be present long enough to be effective. However, a common mode of persistence for viruses is chromosomal integration. This is often undesirable or unnecessary in gene therapy and carries many safety concerns specifically for DNA vectors. Because Ad vectors do not integrate into the chromosome of the host cells, there is no risk that they will permanently alter the host genetic make-up.

3. Broad Tissue Tropism

A wide variety of wild-type adenoviruses have been modified to create Ad vectors, providing a range of different tissue tropisms. More specific tropism has been developed in many therapeutic cases thanks to the genetic manipulation of the knob protein, which is the protruding end of the fiber capsid that is primarily responsible for host cell attachment. This protein is the key to unlock the entry into specific cells through receptor-specific binding. By modifying the knob protein, it is possible to make Ad vectors that can be precisely targeted to specific tissues.

4. Scalable Production

Gene therapy products that cannot be scaled to commercial manufacture cannot be used to treat real-world diseases. As we saw during the rollout of the COVID-19 vaccines, Ad vector-based products can be rapidly scaled to meet market demand. To meet demand for the COVID-19 vaccine, each 5-day production cycle readily delivered over 15 million doses of vaccine to battle SARS-CoV2 virus.

Together, the described benefits of Ad vectors provide a broad and versatile platform to achieve sought-after clinical breakthroughs in the treatment and prevention of debilitating and life-threatening diseases

Clinical applications

Clinical applications of Ad vectors can be broadly split into two categories: vaccines and gene therapies.

Vaccines

Basic research in pursuit of improved Ad vectors revealed that the high prevalence of wild-type adenoviruses in the human population has led to widespread pre-existing immunity, particularly to some human serotypes like Adenovirus serotype 5. Developments in the field have turned this potential drawback into an important feature of Ad vector-based vaccines.

With respect to vaccine development, the main purpose of a DNA-based vector is to deliver epitopes from other viruses to host cells and to ensure production of such epitopes in order to raise an broad and effective immune response against the virus. Over the iterations of development, Ad vectors have become better at delivering increasingly large nucleic acid payloads. In addition, the immunogenicity of some Ad vectors has been tweaked and harnessed to boost the production of pro-inflammatory cytokines that can enhance the humoral and cellular immune responses.

A successful application of this approach is the Ad vector-based Ebola vaccine developed by Janssen. This vaccine, which takes advantage of Janssen’s rare Ad26 serotype, induces specific antibody and T-cell responses against Ebola virus. Clinical results demonstrated that the vaccine elicits a powerful humoral immune response in humans that persists for more than a year. Rapid and durable T-cell responses using Ad26 were also seen in adenovector-based COVID-19 vaccines, which induced strong humoral and cellular immune responses in 100% of clinical trial participants after two doses.

Ad vectors have also been widely used for the production of cancer vaccines. Current vaccine research is focused on prostate cancer, human papilloma virus, colorectal, and pancreatic cancers. In addition to cancer prevention through vaccines, Ad vectors are also used for anticancer therapies.

Oncolytic Virotherapy

Anticancer therapies using adenovirus vectors fall broadly into three main categories:

1. Delivery of Suicide Genes

Many tumor cell types proliferate rapidly and have a dysfunctional p53 tumor suppressor pathway. Ad vectors can be engineered to induce p53 expression inside tumors, triggering cell death. Another successful application has been using Ad vectors to deliver genes that convert a pro-drug into an active cytotoxic agent. For example, the enzyme purine nucleoside phosphorylase converts the pro-drug fludarabine monophosphate into fluoroadenine, which kills proliferating cells. Trials using this enzyme have already been conducted using Ad vectors. The ability of Ad vectors to remain localized is extremely valuable when delivering cytotoxic therapies that can harm heathy cells if the treatment is not constrained to the target cell populations.

2. Delivery of Immune-Regulatory Genes

Ad vectors can also be loaded with genes that stimulate an antitumor immune response. Antitumor interferon-β and interferon-α-2b have both been safely delivered to the lungs of patients via intrapleural injection.

3. Chimeric and Tropism-Modified Oncolytic Adenovirus Vectors

A problem that often arises during cancer therapies is poor recognition of tumors by immune cells and Ad vectors. In this case, Ad vector knob proteins can be modified to bind more strongly to receptors on the surface of the tumor. One example of this is in an Ad vector used to treat ovarian cancer where the entire fiber knob domain of Ad5 was replaced with that of Ad3. The result was targeted ablation of ovarian cancer cells displaying elevated levels of Ad3 receptors.

Adenoviral vectors have come a long way since their initial use several decades ago. Research has shown that they can be used extremely effectively for a number of gene therapy and vaccine applications.

What are the advantages of adenovirus vector in gene therapy?

Adenovirus vectors offer several advantages in gene therapy.

Their large genome allows them to carry significant genetic material, enabling the delivery of larger therapeutic genes, unlike retroviruses, they don’t integrate into the host genome, reducing the risk of insertional mutagenesis. Adenoviruses can transduce both dividing and non-dividing cells, broadening their applicability and elicit a robust immune response, which can be beneficial in vaccine applications.

Is adenovirus gene therapy approved?

Adenovirus-based gene therapies have received approval in specific contexts. One of the most notable approvals is Glybera, which was the first gene therapy approved in the Western world for a rare condition called lipoprotein lipase deficiency (LPLD), approved by the European Medicines Agency (EMA) in 2012, although its high cost and limited demand led to its withdrawal from the market.

Additionally, adenovirus vectors have been explored in various other therapeutic and vaccine applications, with some progressing through clinical trials and gaining approval. It’s essential to check current regulatory databases for the most up-to-date information on approvals.

What is the difference between adenovirus and AAV?

Adenoviruses and adeno-associated viruses (AAVs) are distinct yet central vectors in gene therapy.

Adenoviruses, from the Adenoviridae family, have double-stranded DNA and can cause mild human infections, whereas AAVs – from the Parvoviridae family – are smaller, with single-stranded DNA, and are non-pathogenic. While adenoviruses don’t integrate into the host genome, reducing mutagenesis risks, AAVs occasionally do, often targeting a specific chromosome site. Adenoviruses carry larger genetic payloads and elicit strong immune responses, making them suitable for cancer therapies and vaccines.

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Taking your adenoviral vector product from R&D to the clinic

Taking your adenoviral vector product from R&D to the clinic

Taking your adenoviral vector product from R&D to the clinic

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Nicky Veringmeier

Nicky Veringmeier

Marketing

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Adenoviruses have been shown to be very effective vehicles for delivering genetic material to cells and are therefore in demand to develop gene therapies and vaccine products. The road from early-stage R&D to final production of an adenoviral vector product is well trodden, and there is a lot of detailed information out there to help you on your journey.

That said, taking an adenoviral product to the clinic always requires some process development prior to bringing the vector into GMP. This is based on the many examples in practice where the transgene had detrimental effects on vector yield or purity once inserted into the vector. For instance, the foreign gene may encode for a protein that interferes with HEK293 cell propagation, resulting in low yield of vector particles per cell. Likewise, the protein produced may bind to the Adenoviral vector capsid proteins, which are generally carry a net negative charge that can substantially affect the purification strategy.  A good way of mitigating risk is to seek expertise at the relevant stages of development to fill informational gaps and reduce the possibility of unexpected problems while moving from bench to clinic.

Working with a center of excellence contract development and manufacturing organization (CDMO) is an attractive option for many who embark on the adenoviral production journey. Other than a general vendor type CDMO, A center of excellence CDMO has in-depth experience and can help guide the process by providing practical solutions to challenges that may pop up.   If you are developing a therapy from the very beginning, a “center of excellence CDMO” can often complement your expertise and help you navigate the complexities of the scale-up process.

In this article, we highlight how a “center of excellence CDMO” can help you to smoothly navigate the transitions from R&D to scale-up and clinical manufacturing. The information here will provide you with a stable foundation when you start a conversation with a CDMO, allowing you to identify important traits that will give you a strong relationship going forward.

Common challenges that a CDMO can overcome

Concentration challenges

One of the most important considerations that need to be made early in the product development trajectory is the concentration of the vector needed to be an effective therapy in the clinic (part of Target Product Profile setting).

For adenovector based vaccines, a dose of 1010-1011 virus particles per milliliter typically suffices for systemic administration i.e. intramuscular injection. For oncolytic therapies, either higher or lower doses could be required, depending on the route of administration and the target tissue. For instance, treatment of a wound-bed post cancer surgery may require doses of up to 1013 virus particles per milliliter to effectively deliver a high dose in a confined location with minimal spill-over to surrounding tissue.

At such high vector concentrations, aggregation of virus particles may occur, which reduces therapeutic efficacy. The high concentrations needed for many oncolytic and gene therapies exacerbate this problem. Aggregation can manifest itself in quite spectacular fashion, as concentrated adenovirus preparations become cloudy before “snow” appears on the bottom of the vial. Understanding how adenovirus particles behave and good forward planning are essential to reduce the chances of aggregation.

On the other end of the spectrum, there is also a risk that during the scale-up process the concentration step will not be sufficiently effective, leading to viral titers that are lower than expected. This is a critical issue that can arise due to the significant alterations that are often required during scale-up of concentration steps, such as switching from ultracentrifugation to chromatography.

Since the stakes and capital investment are always higher the further down the scale-up path you are, it pays to address any issues relating to concentration as early as possible.

Release of intracellular DNA

Eukaryotic cells have to be lysed in order to release the adenoviruses, and in the process the release of intracellular DNA is inevitable. The more viral particles needed, the greater the number of cells that must be lysed, and therefore the more host cell DNA is released. Unfortunately, DNA often forms an intricate and sticky web that easily traps adenovirus particles, causing them to aggregate. As discussed in the previous paragraph, adenoviruses are already prone to aggregation, so adding DNA into the mix only increases the risk. The DNA webs also are notorious for clogging filters, which further hampers the purification process. These problems can be circumvented in the process development stages by adding a DNA reduction step such as the introduction of benzonase. With careful quality control, interventions like this can mitigate the negative effects of extracellular DNA.

Process yield & scalability

Perhaps the biggest consideration when manufacturing Ad vectors is the process yield at large scales. In the R&D phase, simply ensuring there is “enough” virus to perform preclinical experiments is acceptable. However, production at larger scales inherently leads to larger losses. During the R&D phase it is therefore essential to prioritize yield. This can be done by reducing the number of empty capsids that are present in your viral preparation and ensuring that your process is ready for the switch to large scale production. This often requires changing from ultracentrifugation, which is a common way to concentrate adenovirus in the research lab but not appropriate for scaling. With technologies used for scale up such as chromatography, it is often difficult to achieve the same yield as ultracentrifugation which is why process development is so important.

How does a CDMO help?

Understanding the different applications for adenoviral vectors is a good way of highlighting how a good relationship with a center of excellence CDMO should work. The center of excellence will have industry experts who can save you a lot of time and expense in developing robust and scalable manufacturing processes for your vector. For example, at Batavia, our in-house experts have extensive experience in developing adenoviral vector-based therapies be it vaccines or oncolytic products. These experts are deployed to relevant projects to help guide the strategy and ensure the highest likelihood of manufacturing success.

Clear communication is a must for a good center of excellence CDMO. Clearly articulating the challenges and opportunities of a scale-up project is the only way to make effective progress. While good communication may seem less relevant than the technical capabilities of a prospective CDMO, it is nevertheless important and very easy to assess early on your interactions. Pay close attention to how your CDMO communicates. Make sure that misunderstandings are quickly resolved, and that communication is clear and timely. The way a CDMO communicates and structures their meeting and interactions is a reflection of how they operate, so if you are not satisfied, it’s best to move on.

A good CDMO should bring balance and clarity to the scale-up project. When you partner with a center of excellence CDMO, you should feel confident that you are in good hands. You should also feel that you acutely understand the process going forward, including the potential risks.

At some point when moving from R&D to scale-up and production, you will meet a whole range of different regulations that have to be thoroughly studied and strictly adhered to, if your adenovirus vector is to make it successfully into the clinic. A good center of excellence CDMO has experience with the relevant and most up-to-date regulations and requirements, and will help you navigate the complex landscape of rules and paperwork. Always ask about track record.

Choosing a CDMO

If you decide that working with a center of excellence CDMO is the right path for you, the next question is who should you choose? Fortunately, the CDMO field is competitive, and you do have a choice. It’s important that you exercise this choice and do your due diligence by thoroughly researching and interviewing your CDMO candidates. Pay close attention to the way they communicate with you and how they discuss your project and bring up challenges. Most importantly pay close attention to the quotation and make sure to read the small footnotes to understand what is included in price and what is excluded and needs to be paid additionally.

It’s never too early to begin discussions with a partner to help you scale your adenoviral vector product. Even informal conversations early on can give you insights and help you make decisions that will have a positive impact on the future of your project. To start with, why not book a call with one of our experts. We’re looking forward to hearing about your project and you can be sure that we’ll give you clear advice and an all-included costing overview for your project.

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Driving Down COGs of Viral Vector-Based Biopharmaceuticals

Driving Down COGs of Viral Vector-Based Biopharmaceuticals

Driving Down COGs of Viral Vector-Based Biopharmaceuticals

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How do you keep cost of goods (COGs) for viral vector-based medicines within reason to develop a product that is both affordable and financially viable? 

In this 3-part series we take a deep-dive into how in silico cost modelling is being used to pinpoint the cost-drivers in development and manufacturing of viral vector-based vaccines and therapies. We’ll explore how better and earlier cost assessment can help biopharmaceutical companies improve decision-making throughout the development process, establish more robust and financially sustainable manufacturing processes, and keep COGs under control.

Viral Vector Affordability

From vectored vaccines to gene therapies to oncolytic agents, viral vectors are at the heart of many exciting scientific and medical breakthroughs. Yet companies in this sector face a difficult balancing act: how to keep these potentially life-changing treatments affordable for patients and payers, while still producing a product that is financially viable. The ongoing rapid expansion of markets and population sizes for viral-based treatments only intensifies the challenges, as manufacturers scramble to scale production capacity, often pushing traditional process technologies and facilities to their limits. In this high-stakes, high-pressure climate, success hinges on reaching new pinnacles of cost-efficiency and productivity in development and manufacturing of viral vectors.

The Cost of Cell & Gene Therapies

Gene and cell therapies: harsh economic realities put COGs in the spotlight.

Over the past decade, sky-high prices for emerging gene therapies have evoked public outcry.  At $1.2 million per patient, jaws dropped when Glybera was launched in 2012. Less than 3 years later uniQure and its European partner Chiesi withdrew it from the market amidst rumors that only a single dose had been sold for commercial use.[1] While the small patient base affected by this rare disease had a lot to do with the drug’s commercial implosion, high COGs were almost certainly part of the mix that made Glybera a losing proposition.

 Thanks in large part to the adoption of innovative reimbursement schemes, more recent AAV1-based gene therapies such as Zolgensma for spinal muscle atrophy ($1.2m per dose) and Luxterna for inherited retinal disease ($425K/eye) have actually exceeded investor expectations, despite their higher price tags.[2],[3] Nevertheless, cost-effective manufacturing remains a challenge, and the spotlight on pricing practices and COGs contributions is not likely to fade anytime soon.

The trend towards higher doses for viral vector-based therapies is intensifying the need for greater cost-efficiency and economies of scale in clinical development and manufacturing. Take Sarepta Therapeutics’ investigational gene therapy for Duchenne’s Muscular Dystrophy, for example.  By some estimates, the cost of manufacturing a single dose of 8×1015 vg could be as high as $100,000 with conventional manufacturing platforms and facilities.[4] While such high COGs may not lead to an affordability crisis when targeting relatively small populations with one-time curative treatments, the commercial and logistical propositions become less tenable at larger scales.

As advances in cell and gene therapy technologies enable targeting of much larger patient populations and more mainstream markets, minimizing COGs and maximizing productivity will become even more crucial. Oncology-directed gene and cell therapies, for example, will have to compete with more traditional drugs, including biosimilars, in terms of pricing and cost-effectiveness.

 

COGs Challenges in the Vaccine Industry – A Different Dynamic

The challenges and cost implications of large-scale production are already acutely felt in the vaccine industry. In developing and low-income countries, cost-per-dose and manufacturing capacity are major barriers to vaccine access.  Efforts to roll out rotavirus vaccines on a global scale are a good example.

Despite clear evidence that existing rotavirus vaccines can prevent fatal gastroenteritis, nearly 60 million children worldwide still lack access—most of them living in just 10 countries.[5] In the course of developing a scalable manufacturing process for an improved rotavirus vaccine, researchers estimated that COGs would need to be ≤$3.50 per course of three doses in order to meet predicted market requirements.[6] This is in stark contrast to more affluent cell and gene therapy markets, where bringing COGs of some AAV-based gene therapies down to $10,000 per dose would be seen as a significant achievement.[7]

The COVID-19 pandemic brings the need for more equitable global access to vaccines into sharp focus. With the realization that “no one is safe until everyone is safe,” the urgency of developing more scalable and cost-effective processes for manufacture of viral vector vaccines has never been greater.

Gaining insights with in silico cost modeling

Understanding how various technology and process choices will affect COGs is crucial to develop a robust, high-yielding and cost-effective manufacturing process.

Often the cost implications of these choices are discovered too late—after the clinical manufacturing process has been locked down. This can lead to delay approval in latter stages have devastating consequences for the development program.

In silico cost modeling of manufacturing processes is a powerful tool that can help product developers identify the main cost drivers early, so that they can make more informed, data-driven design decisions throughout the development process. In the next articles of this series, we’ll take a closer look at what cost modelling entails and the benefits it can bring to viral vector process development.

What is the average COGS in pharma?

A report published by Hardman&Co in 2021 estimates that the weighted average COGs for the pharma indutry was 25.7%, caused in part due to complex processes and inefficient manufacturing.

Why are biopharmaceuticals are expensive?

Biopharmaceuticals are expensive due to the high costs of lengthy research and development, complex production processes, regulatory approvals, and patent exclusivity. Additionally, developing cheaper alternatives, like biosimilars, is more challenging than with traditional drugs.

How much does biopharmaceutical development cost?

Developing a new drug – from developing a drug candidate through to clinical trial – can typically exceed $2 billion (USD). Although this cost continues to rise, R&D costs have typically decreased after the COVID-19 pandemic.

What are the challenges with biopharmaceutical manufacturing?

Biopharmaceutical manufacturing faces challenges like the intricacy of working with living cells, ensuring product consistency and purity, maintaining sterility, scaling up production, and meeting stringent regulatory standards. These complexities result in higher costs and require specialized expertise.

Related

New Test for Rapid and Low-cost Quality Control for Polio Vaccines

Batavia Biosciences has developed a qPCR method that can specifically detect mutations that can accumulate in poliovirus strains during vaccine production. The test demonstrates a sensitivity level highly comparable to current best practices. The novel test has been accepted for publication in the international, peer-reviewed prestigious Vaccine journal.

Tackling the capacity bottleneck in downstream processing of viral vectors

Written by expert: Evert, Associate Director DSP

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.

Low-cost viral vector manufacturing

High-throughput screening for viral vectors

Viral vector manufacturing

Thermostable viral envelope protein formulation

Maximizing protein expression