Vaccines Bioprocess Development & Commercialization Workshop

Current FDA regulations and guidance define pathways that facilitate product development and licensure. New guidance is created and made available to industry and regulatory stakeholders to ensure the Agency is both responsive to emerging public health needs and to encourage the use of advancements in technology to improve product development. In response to the recent pandemic, guidance documents were created that defined accelerated product development mechanisms that allowed for enhanced interaction between the sponsor and the FDA review team, flexible submission schedules, and, in some case, shortened review timelines. These pathways were created to better support development of new products where a defined unmet medical need exists. In addition, in response to the recent pandemic, legislative initiatives directed the creation of two new guidance documents that will support future product development, review, and licensure. One on the use of platform technologies and the second on the use of advanced manufacturing technologies. This presentation will highlight the history of regulations related to vaccine development, review activities associated with vaccine development during an ongoing pandemic, and an introduction to the implementation of two new guidance documents

The CBF has over 20 years experience producing biological Investigational Medicinal Products (IMPs) according to the principles of GMP for early phase clinical trials. We hold a Manufacturer’s Authorisation for Investigational Medicinal Products (MIA (IMPs)) from the Medicines and Healthcare products Regulatory Agency (MHRA), which allows us to manufacture viral vector vaccines and advanced therapy medicinal products (ATMPs), including gene and cell therapy products. All IMPs are manufactured and released in accordance with the European Clinical Trials Directive (2004). The facility can also import IMPs from outside the EU for use in clinical trials within the European Union. We aim to provide the link between academic research and clinical drug development, to allow all our collaborators to make rapid progress into clinical trials.

In this presentation I will discuss the particular challenge of the cost-effective manufacturing of novel, one-off, small batches for clinical delivery and of operating to cGMP with phase appropriate validation, using a risk-based approach. I will present some descriptions of recent analytical adoptions, and improvements to the processes that we use to manufacture adenoviral vectors, and a case study of manufacture of a new vaccine type for the CBF, with lessons learned during the tech transfer and validation phases that can be applicable to future campaigns.

An integrated approach is described for accelerating process development workflows. The approach involves five strategies which include increased mechanistic understanding, process intensification, and plug-and-play modules with integrated control and monitoring. Automated high-throughput microscale technologies are described for process research and development. Deployment is facilitated by accompanying each physical modular system with a dynamic mechanistic model. A process data analytics strategy is described in which the best methods are automatically selected based on the data characteristics and user objectives. The strategies are illustrated in applications to vaccine manufacturing systems.

The development of vaccines still faces significant challenges in the post-COVID era, from complexed competition landscape and constant pressure to reduce costs, all the way to vaccine hesitancy and uncertainty of geopolitical shifts. Other challenges include regulatory harmonization, the need for immediate access to vaccines, and the impact of pandemics on vaccine development timelines. Despite these challenges, the development of vaccines remains crucial for public health and disease prevention. To address these challenges, new approaches and technologies are being explored, such as platform technologies that can expedite vaccine development, Process Analytical Technologies (PAT) to monitor process in real time, and predictive modelling to establish product stability. Future opportunities for vaccine manufacturing also include continuous manufacturing, decentralized manufacturing, and the use of micro-array patches. Investment in science, academia, and industry is crucial for the future of vaccine development.

The success of mRNA-LNP technology in enabling the rapid development and production of COVID-19 vaccines—and the recent approval of an RSV vaccine—has opened the door to a wide array of applications in vaccines and therapeutics targeting infectious and non-infectious diseases. Compared to traditional biologics, mRNA-based manufacturing offers a streamlined, cell-free process with a plug-and-play design, allowing for rapid adaptation of sequences and valencies across different vaccine candidates. This inherent flexibility provides significant advantages in terms of speed, scalability, and efficiency.

However, the platform’s reliance on several specialized raw materials—such as enzymes, nucleoside triphosphates, plasmid DNA, and lipids—introduces unique challenges. To fully realize the potential of mRNA technology, Chemistry, Manufacturing, and Controls (CMC) teams must establish robust, long-term strategies for sourcing, characterizing, and controlling these critical inputs.

This presentation will address essential considerations, including:

· Phase-appropriate quality and regulatory requirements

· Strategic sourcing and supply chain resilience

· Identification, characterization, and control of material attributes critical to process performance

Post approval changes are common for licensed vaccines.  Such changes to the license may be done to implement cost-saving process improvements, change a formulation, or put a new manufacturing site into service.  Use of a comparability protocol can speed implementation of changes.  This presentation will introduce the concept of comparability protocols and discuss two vaccine case studies that used comparability protocols to implement changes to the license.

Design for Manufacturability (DFM) is a common practice in many industries to reduce inefficiency in scaling production, lower costs, and improve time to market. Vaccine design, in contrast, has predominantly relied on whatever nature provides. With advances in systems biology and genome engineering, there is an opportunity to rethink how we design subunit vaccines with the end in mind, and simplify production processes, improve yields, and lower cost of goods manufactured.  This talk will spotlight three vignettes that show how upfront molecular and cell engineering can make vaccine candidates that are more manufacturable while retaining immunogenicity. First, we’ll explore a trivalent rotavirus subunit vaccine where vector engineering and conservative sequence changes reduced the number of operations by more than 50% and enabled a consolidated single production process for the trivalent vaccine.  Next, we’ll look at how historical sequence analyses and rational engineering optimized the production of a SARS‐CoV-2 receptor-binding domain by 100x compared to the ancestral sequence, but also unexpectedly broadened neutralizing responses across emerging variants. Finally, we’ll consider how to modularize the production of virus-like particles (VLPs)  in a way that allows tunable modularity and is amenable to low-cost platform continuous production. Together, these examples demonstrate how incorporating DFM in vaccine discovery could transform their development to enable lower costs and improved products amenable to state-of-the-art manufacturing to improve the affordability and availability of these products.

There is an urgent need to improve virus-like particle (VLP) biomanufacturing processes to prevent VLP vaccine shortages and reduce cost of goods manufactured. As ~20-200 nm particulate antigens with repetitive surface structure, VLPs drive robust immune responses with high protective antibody responses, making them a very compelling platform for preventative and therapeutic vaccines. Most clinically approved vaccines against Hepatitis B (HBV), Plasmodium falciparum, and HPV are VLP vaccines produced inside yeast cells. Although VLP production in yeast is more cost-effective than in other cellular hosts, the process yields from routine production in fed-batch systems have still resulted in extremely high costs of goods manufactured (COGsM). These high manufacturing costs beget expensive vaccines that are inaccessible to potential beneficiaries in the Global South, including commercial products like Gardasil-9, which has less than 30% uptake in African adolescent girls despite HPV prevalence in Africa being nearly twice that of other continents worldwide.

Sunflower is pioneering an innovative perfusion fermentation approach for the production of VLPs and other protein biologics using fully-automated continuous bioprocesses. Perfusion fermentation enables cultures to build a healthy biomass through continual nutrient replenishment and removing a cell-free harvest (including waste products) from the reactor. Here, we will present data showing the perfusion fermentation of Pichia pastoris using the Daisy Petal TM Perfusion Bioreactor System for intracellular expression of multiple serotypes of a proprietary HPV VLP candidate vaccine. The space-time yield (STY) of the VLPs achieved using perfusion fermentation of yeast was consistently higher than the STY of VLPs achieved using fed-batch processes and particles achieved were capable of inducing robust anti-virus neutralizing antibodies in mice. Given the influence of STY on COGsM, we believe that perfusion fermentation has significant potential to enable lower vaccine costs to patients and enable regional production capabilities as part of small-footprint distributed manufacturing facilities.

Every year, millions of people in low-and-middle-income countries (LMICs) continue to die of diseases, like tuberculosis and malaria, that few people now experience in high income countries. The importance of developing innovative solutions to tackle these diseases has been highlighted both by recent changes in government aid that will exacerbate the reach and lethality of these diseases as well as by the Covid pandemic which laid bare the inequitable access of many underserved communities to important preventative and therapeutic tools like vaccines. However, the investment incentives for discovery, development and manufacturing of innovative products that address significant global health needs are not always in place for traditional pharmaceutical and biotechnology companies.

The Gates Medical Research Institute is a non-profit medical research organization dedicated to the development and effective use of novel biomedical interventions to address substantial global health concerns. There are a number of key challenges to enable LMIC access to effective biopharmaceuticals, even with development funding. First, no single organization can do this work alone. Partnerships and collaboration models between companies, funding bodies, non-profits and international organizations are key to tackling the most devastating diseases. Our work with our tuberculosis products, both vaccine and therapeutics, illustrates the power of partnerships.

In addition, scientific approaches that work in high income countries or work for a similar disease may not be successful for LMIC diseases. Novel solutions, tested in the target populations, may be essential. Development of a shigella vaccine that is effective in the smallest children who are most vulnerable to that disease has proved particularly difficult. We developed robust manufacturing processes that allowed the production of a unique and promising synthetic glycoconjugate shigella vaccine, so it can now be tested by a partner in an endemic region. Furthermore, to ensure accessibility in LMICs, it is imperative to lower cost of goods (COGS). We are using a systematic approach to reduce the drug substance (DS) manufacturing cost of goods for our prophylactic monoclonal antibody (mAb) for malaria. By combining a “real-world” quote-based approach and detailed process economic modeling, we evaluated the feasibility and opportunities of achieving the cost target for this product. We believe that all lives have equal value and that inspires us to meet the challenges of delivering robust, effective, low cost healthcare solutions for those in greatest need.