The COVID-19 pandemic has caused significant changes, both disruptions and accelerated development. Lessons learned can inform practices from the production floor to regulatory guidance for the commercialization of future therapeutics and vaccines. This presentation looks at how organizations adapted to the unprecedented critical need to get to market with life-saving vaccines; and how process development; manufacturing/operations/facilities; partnerships; and regulatory change can accelerate development in the future.

Impact of COVID-19 to the supply chain for raw materials and consumables created major challenges for biopharmaceutical manufacturers. Unprecedented demand for these items as a result of rapid acceleration of manufacturing of vaccines and therapeutics as well as shortages induced by plant shutdowns, supply disruptions of plastics and lockdowns in certain countries converged together to create a “perfect storm”. Single-use facilities are by nature heavily dependent on steady supply of consumables. In this presentation, we will describe how proactive planning, strong supplier relationships, creativity to find alternatives, process flexibility and risk tolerance can work to ease the supply constraints and continue to deliver to patient needs.

After a challenging year 2020, it is evident that rapidly evolving diseases call for Bioprocess Development at Pandemic Pace. In the case study at hand, we demonstrated accelerated development of an IgG antibody production process by parallelization of early development work packages and by relying on producer pool fermentations up to phase 1 clinical supply.

OriCiro® Cell-Free cloning system wipes the bottleneck of conventional E. coli cloning and It just two steps in vitro.

OriCiro® 's enterprise solution for Cell-Free Plasmid DNA Manufacturing Service has capable to shows in the following benefit.

1. Rapid : Reaction by several hours, isothermal and enzymatic reaction,
2. Safety : No endotoxin, No GMO, No antibiotics and antibiotic-resistant genes and
3. Process enhancement : Significant downsizing for upstream and downstream facility

AAV Reference materials for gene therapy has been lacking, resulting in poor inter-lab and inter-product comparability. Vigene has developed a standardized production protocol and analytics panel for AAV1, AA2, AAV5, AAV6, AAV8 and AAV9 empty and full capsids to facilitate the testing of AAV gene therapy products. The production process and analytical results will be discussed.  Some lessons learned from this year-long endeavor will also be shared.  Key Topics:Production process of AAV Reference Materials; Analytical results of AAV Reference Materials.  

Developing high-yielding, robust, scalable and commercially viable processes to manufacture sufficient quantities of viral vectors presents challenges. This work focused on development of two suspension-based AAV production processes, scaled from shake flasks to ambr250, 10L, 50L and 200L stirred tank bioreactors. Scale-up presented challenges yet through high-throughput optimisation utilising a DoE approach, performed using the ambr250, high-yielding and scalable processes were developed with titres maintained up to 200L scale.

Pressure to reduce time-to-market and production cost of viral vectors and cell-based therapeutics is driving demand for technologies that combine the greater yield efficiency and viable cell harvest of adherent platforms with the scale and automation of suspension systems. Dr. Shyu will present a new intensified FBR technology that has demonstrated a multi-fold increase in viral vector yield per cm² and greater than 90% transfection rate and cell harvest efficiency.

Evolution of 2-L single-use bioreactor design customization and assessment, with performance comparison to traditional glass bioreactors, will be presented. Multiple cell lines, different media and modes of operation were examined to support implementation of single use across pipeline projects.

Bioprocess development requires multiple process scales to enable the collection of large data sets that represent the commercial scale process of the product. This presentation reviews the scale down of a microbial fermentation process to the Sartorius Ambr 250mL single use bioreactor system and the associated time and cost savings when generating process characterization data at this smaller scale.

The production of human monoclonal antibodies is not free of viral contamination risk due to adventitious agents in raw materials, cell substrates and environment. Such risk is generally mitigated by a series of unit operations. Mostly, these unit operations are time and resource expensive. Machine learning methods can potentially help streamline the development and optimization of viral clearance steps. The evaluation of machine learning methods for process understanding, process contextualization and predictive modeling for viral clearance steps is the focus of this study. A case study on low pH viral inactivation will be included in the presentation.

A digital twin is “a real time digital replica of a physical device”. It is a digital informational construct of a real physical system that communicates in real time with its physical counterpart. A digital twin aims to mirror the life and predict the evolution of its corresponding physical asset and to reach this goal it utilizes state-of-the-art mechanistic and/or hybrid models, advanced sensors, connected objects and artificial intelligence to do so. This talk is concerned with the development of digital twins in GSK for development and control of vaccines production process.

Microalgae are versatile photosynthetic organisms poised to become a sustainable platform for therapeutics, vaccines, biofuels, and plant-based protein. However, bioprocessing challenges continue to limit production at commercial scales. While the field has benefitted from advances in bioreactor design, strain selection, and bioengineering, the viability of algae-based products seems to always be just out of reach. This presentation reviews R&D accomplishments in algal biotechnology and identifies major hurdles to successful commercialization.

Microbioreactors are a promising technology to accelerate biologic drug development. In aerobic cellular respiration, a potential limit to the productivity of such systems is the transport of oxygen from an external gas to the most oxygen-deficient cells, and the potential for excessive spatially localized dissolved oxygen which can result in cellular damage. A mechanistic model is presented for the spatiotemporal transport of oxygen through a gas-permeable membrane to the cells within a microbioreactor. The model is used to design an on-line estimator for the oxygen uptake rate of the cells, the specific cell growth rate, and the specific oxygen uptake rate. The estimates are fed to a model predictive control formulation that improves the spatial control of dissolved oxygen during cell growth by more than 30% compared to a PID controller.

The application of single use technology in biologics research and production has increased enormously over the past ten years. A large variety of single use fermenters with differences in terms of mixing, power input, gassing strategy, and maximum work volume are presently being offered. A standard characterization method based on conventional stainless steel and glass bioreactors is developed. However, this characterization method needs extra work for measurement of standard engineering parameters, like volumetric oxygen transfer coefficient (k_L a), and lacks compatibility and comparability of SUF and steam in place fermenters (SIP). In this presentation, we will present a method through generation the ratio (%) of k_L a alike between SIP and SUF, from analyzing of existing data. Two scenarios were analyzed, one at low demand standard density growth, and the other at high density growth. The results matched with performance of SUF to SIP very well. This enables a practical approach for evaluation of SUF as replacement of SIP for production of biologics in diagnostic business.

The BioPhorum Plug and Play Standard was conceived and developed through an industry-wide collaboration to enable the rapid deployment of modular equipment in biopharmaceutical facilities. The standard, co-developed by equipment providers, automation suppliers, and end-users, provides a common structure for defining an equipment’s automation capability. It utilizes existing and proven industry communication standards, eliminating the need for custom communication interfaces. BioPhorum estimates that a manufacturer utilizing the standard would save considerable costs in engineering and validation during the construction of a new manufacturing facility. Eliminating custom interface development can save weeks and even months in deploying automated equipment.

Besides conventional offline analytical testing for AAV production at bench scale, a digital differential holographic microscopy system was developed to monitor suspension cell culture systems. Key process parameters including viable cell density and transfection/infection efficiency were determined at real-time for the production process. This process analytical technology (PAT) holds promise for future upstream process optimization for gene therapy products.

An improved understanding of the culture environment within bioreactors is essential for developing robust, high yielding processes. We will explore the usage of advanced process control and predictive modelling in mammalian cell cultures to automate and optimise bioreactor feeding and control strategies. A series of case studies will cover topics including utilising integrated PAT tools for automated at-line feeding and using machine learning to control and refine bioreactor set points.

Digitalization, data enablement and analytics are key drivers to accelerate bioprocess development. In this talk, the operationalization of our digital/data strategy through a structured and agile program delivery will be discussed, covering 1) unified data management and IT/OT infrastructure to improve data access, sharing and integration, and 2) analytics and control capabilities to increase process visibility, comparability and predictability, as well as productivity and quality.