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.