Vaccines Bioprocess Development & Commercialization Workshop

Current regulations and guidance define several pathways that facilitate expedited product development.  These regulatory mechanisms allow 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 response to the emergence of viruses that have caused regional and global public health emergencies, Ebola virus in 2014 and SARS-CoV-2 in 2020, respectively, the Agency conducted expedited reviews based on existing review mechanisms, but also utilized additional regulatory resources to facilitate the availability of safe and effective vaccines to help prevent disease from each of these viruses.  This presentation will highlight the history of regulations related to vaccine development, review activities associated with vaccine development during an ongoing pandemic, and how lessons learned will be used to facilitate vaccine development and availability in the event of future public health emergencies.

The 2014 outbreak of Ebola virus disease in West Africa highlighted the lack of preparedness for combating infectious disease outbreaks. Since 1976, vaccine development had proceeded slowly and no candidate vaccines had progressed further than phase I trials. Ebola is only one of many known viruses with the potential to cause outbreaks. With the support of the WHO in identifying priority pathogens, and the formation of CEPI to provide funding, vaccine development was initiated with the aim of having vaccines available in readiness for future disease outbreaks.

‘Disease X’, to represent a disease caused by a previously unknown pathogen, was also considered. In the first days of 2020, the first ‘Disease X’ outbreak, caused by a virus later named SARS-CoV-2 occurred. Vaccine developers found ourselves attempting to put into place plans that were at an early stage of development, had not been funded and had not therefore been tested. Rather than working to produce a vaccine which could then be deployed in the ‘outbreak area’ we found ourselves attempting to develop a vaccine against a novel pathogen that was causing a pandemic whilst we ourselves were in the grip of that pandemic with every aspect of our work affected.

This presentation describes the mechanistic modeling and control of the manufacturing of viral, virus-like particle, subunit protein, and mRNA vaccines. After an overview of the progress for all of these vaccine types, the use of perfusion or continuous culture to increase productivity is discussed. Then a detailed description is provided on mechanistic models, sensor development, and control for continuous viral vaccine manufacturing in suspension culture. Results demonstrate smooth quasi-steady continuous operation over an extended period of time and good agreement between a mechanistic model and data for experiments carried out at a local contract manufacturing organization.

The development and manufacturing of vaccines has rich history and evolution, driving, adopting or adapting the science and technology boundaries of the time. As a vaccine progresses through the life cycle, from discovery to stablished product to end of life cycle, different factors dictate the decisions and paths organizations take. From the constraints of the scientific and technical knowledge, to the economics of production and distribution, our industry achieves a careful balance to ensure the continued delivery of life-saving vaccines.  In this presentation, we will look through the lens of the manufacturer at factors playing significant roles as a vaccine candidate transitions from development to commercial manufacturing, from launch to mature product incorporating advances in science, technology and regulatory science and to a final transition at the end of the product life cycle.

Significant investment is being made in developing mRNA-based vaccines for infectious diseases such as Influenza and RSV with an expectation of speedy development with high efficacy. There are, however, several CMC pre-requisites to enable these expectations.

• Standardize mRNA and LNP design platforms to maximize therapeutic index while ensure manufacturability.
• Continuously build product understanding through analytical and biological characterization in pre-clinical and clinical settings.
• Establish phase appropriate control strategy that incorporates latest product understanding and regulatory expectations.
• Develop and standardize designs of manufacturing process and formulations that meets control strategy while retains flexibility to capture innovation in product and process platforms.
• Establish end to end manufacturing & QC footprints for clinical and commercial launch of a dynamic product portfolio; This network should include external sourcing and/or internal manufacturing of special raw materials at appropriate levels of quality, scale, and cost.

This presentation will summarize status of CMC platforms and describe specific elements of   mRNA-LNP to consider in designing control strategy, manufacturing process, thermostable formulation, and associated technologies. Additionally, the requirement to build a deep understanding of critical materials will be emphasized. The enabling role of data continuum infrastructure and data science tools to efficiently optimize processes will be noted.

Here to be presented is case study on Pfizer’s journey to supplying COVID 19 Vaccine at unprecedented pace & scale. Kevin will give a high-level overview of Pfizer’s and BioNTech’s mRNA vaccine technology and bring us through us some of the key process innovations which facilitated rapid process development and scale up which were required to provide COVID 19 vaccine at a pandemic supply level.

Translational development of new concepts for vaccines from discovery to the clinic has required unique processes tailored to the characteristics of each immunogen and final vaccine product.  For recombinant vaccines, each immunogen may have its own properties and specifications that confer immunogenicity, and development usually begins with optimizing production of a selected sequence, followed by serial development of steps for recovery of the antigen.  With these materials in hand, product development follows formulation development and stability studies.  This approach to process development is linear, with limited feedback into prior stages including discovery and early evaluation of candidate vaccines.  Iterative learning from one vaccine to another can be also limited and process development often starts new each time.  This talk will present an integrated platform-like approach to recombinant vaccine development that incorporates an iterative design process emphasizing molecular design of antigens, strain engineering and integrated straight-through purification for recombinant proteins with examples for rotavirus and SARS-CoV-2 vaccine candidates.

Delivering effective viral vaccines to the market on time is critical for preventing and controlling infectious diseases. Traditional manufacturing processes are highly complex, require extensive process development efforts, and tend to suffer from a lack of scalability to rapidly reach commercial scale capacity. Advances in integrated and automated manufacturing technologies result in cost-effective, scalable, and highly productive processes. Those technologies are considered as flexible by design as they can accommodate various expression systems, vaccine applications and capacity requirements, while streamlining the vaccine development process. Structured fixed-bed bioreactors can achieve high cell densities with superior specific cell productivities through homogeneous cell distribution and media flow. They sustain reproducible results from small to large scale in a reduced volume and simplify the time to scale-up. Additionally, the integration of upstream and midstream process units with a highly intensified fixed-bed bioreactor provides automated continuous processing, drastically reducing the complexity, footprint and CAPEX while meaningfully reducing the cost per dose. In this presentation, the speaker will focus on technology innovations leveraging process intensification and continuous processing to deliver capacity at low footprint, process flexibility and accelerated development and scale-up timelines.

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.

mRNA/Lipid Nanoparticle (LNP) technology has evolved rapidly over the last decade, significantly changed the vaccine and therapeutics landscape, and recently proven its technology potential with commercial successes in two COVID-19 vaccines. Catalent has contributed to the evolution of this exciting technology field since 2016, by helping clients to develop, manufacture, and test vaccines or drugs for cancer, infectious disease, or genome editing applications. In this presentation, we will share our process development and manufacturing experience in the workflow from DNA, mRNA, LNP, to fill finish. Unique challenges in developing and manufacturing this nascent technology will be covered. Outlook on further evolution of DNA and mRNA technology to increase product quality and reduce development time will be discussed. Challenges and opportunities in LNP processing and stabilization will be discussed.

At the Bill & Melina Gates Foundation we envision a world where every person has the opportunity to live a healthy, productive life.  To that end the foundation invests heavily in vaccines, from discovery, to manufacturing, delivery and policy, an effort that has aided the reduction of global measles, paralytic polio, and COVID-19 disease burden. We are currently facing the looming existential threat of climate change, which affects the most basic requirements of health: clean air, safe water, sufficient food and adequate shelter. Vaccine discovery, development and commercialization can all play a role in mitigating the risk of climate change related health crises. Maximizing manufacturing efficiency, by producing a higher yield per unit of each input, has potential to dramatically reduce cost of the final product. New and evolving tools in computation, materials science, and vaccine delivery similarly provide opportunities for efficiency gains across multiple dimensions, including minimizing development time, streamlining tech transfer activities, and maximizing protective responses and vaccine coverage while minimizing injection pain and adverse events. New technologies that control vaccine release may be deployable to maximize efficiency for existing vaccines and achieve robust protection against intractable infections like HIV and malaria.

Discussion Moderator:

Barry C. Buckland
University College London

Discussion Panelists:

Dame Sarah Gilbert
University of Oxford

Robin Levis
U.S. Food and Drug Administration

 Judith Maxwell Silverman
The Bill & Melinda Gates Foundation

Tara Tagmyer
The Bill & Melinda Gates Foundation