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Over the past 15 years we have seen the widespread adoption of single-use technologies as a means to improve the efficiency and economics of new manufacturing processes within the Biotech sector. As part of the strategy towards further improving bioprocesses, there has been a great deal of interest and activity in Continuous Processing. By integrating single-use technologies into innovative process solutions for downstream processing, Pall Biotech is now able to offer a portfolio of products designed for end-to-end purification of biologics from the bioreactor. This presentation will demonstrate the scalability of this approach and demonstrate its utility to improve future bioprocesses.
The biopharmaceutical industry is known for its long time-to-market and for requiring large resources and time investment for product development. The type of activities required at the start of a biopharmaceutical product development focus mainly on designing a suitable process for manufacturing as rapidly as possible material to be tested in pre-clinical and clinical trials. The number of development and GMP batches is at this stage typically limited. This is followed, upon success in early clinical trials, by a process optimization phase, which aims at increasing yields while reducing costs-of-good. Moving on towards late stage development, the manufacturing process needs to be characterized, meaning that its robustness to produce the desired product quality when operated within certain process ranges needs to be demonstrated. This phase is a major component of process development as it translates into generating large numbers of development batches using elaborate analytical methods and advanced statistics, in order to fully study the relations between the manufacturing process and product quality.
Janssen Vaccines has transitioned over the last 3 years from being focused on early stage process development, to being able to accommodate and run full late stage development programs. Janssen Vaccines also embraces the principles of Quality by Design (QbD) in its development programs, where science and risk-based approaches are used as a systematic way to build product and process understanding.
In this presentation, we present the implications of this transition from early to late stage development, with the case-study of the QbD-based characterization of a perfusion-based PER.C6® cell culture process for Adenovirus vaccine production.
Computational Fluid Dynamics modeling and in-depth scaling calculations have been utilized in partnership to generate data to support equipment design and facility fit during commercialization of a fermentation and primary recovery process for a vaccine candidate across multiple technical transfers. This analysis utilizing representative computer models for tank configurations, supplemented with traditional computational scaling approaches (ungassed P/V, gassed P/V, kLa, etc.), ensures full knowledge of a tank’s mixing and oxygen transfer capabilities allowing process understanding and robust manufacturing across technology transfer to multiple sites. Implementation of this approach across process steps as well as manufacturing sites allows increased knowledge prior to use in a process and/or prior to construction of a new vessel, therefore contributing to successful process transfer with reduced risks upon scale-up/scale-down and new facility introductions.
Vaccines based on viruses and viral vectors are becoming increasingly important for prevention and, more recently, for treatment of a large number of diseases. Furthermore, viral vectors such as adenovirus (AdV), adeno-associated virus (AAV), and lentivirus (LV) are also being used in gene and cell therapy.
As competition and cost pressure in the global biopharmaceutical and vaccine industry increase, the choice of manufacturing technology is gaining importance. The manufacturing processes and technologies are critical to enable cost-efficient and scalable production of safe and efficacious clinical-grade virus products.
This presentation will focus on manufacturing of AdV. We have combined experimental work and process economy calculations, from AdV production in cell culture to purified bulk product. An efficient and scalable process for AdV production was developed by evaluation of each process step. First, HEK293 suspension cells were adapted and evaluated in different serum-free cell culture media. Cell culture conditions were optimized for AdV production and tested in different single-use cell culture bioreactor systems. Filters and conditions for clarification as well as concentration and buffer exchange by tangential flow filtration were optimized. Alternatives for the downstream capture step were compared, including both chromatography resin and membrane formats. Finally, core bead technology was evaluated as an alternative to size exclusion chromatography for the polishing step before final formulation. For downstream purification, different process alternatives were compared regarding virus load capacity, recovery, and purity. Based on analytical data, we propose a robust and scalable process with a favorable process economy.
Despite their low costs, rapid deployment and flexibility, the current Single Use facilities are limited by their output, typically 500 kg/year for a 6 x 2000 L facility at 3 g/L Fed Batch titer. This also limits their usefulness for commercial scale manufacturing of multiple midsize portfolio products. Upstream process intensification can solve this limitation. With consistent effective titers of 10 g/L and beyond, annual outputs of 1500 kg/year can be realized from Single Use facilities so they become an even more attractive option for commercial manufacturing of multiple products.
To this point however the development and scale-up of intensified upstream has been cumbersome and time consuming. In this presentation a platform of upstream process intensification tools and technologies are shown, that can greatly speed-up and improve process development, scale-up and commercial scale process control.
Examples will be shown including an effective titer boost from 3 to 10 g/L in 12 days of culture, using commercially available platform tools, including cell line, media, process development tools and commercial scale manufacturing tools.