Disposable Bioreactors II

Orbitally shaken single-use reactors are promising reactors for upstream processing, because they fulfill three general requirements for single-use equipment. First, the design of the disposable parts is inherently simple and cost-efficient, because no complex built-in elements such as baffles or rotating stirrers are required. Second, the liquid distribution induced by orbital shaking is well-defined and accurately predictable. Third, the scale-up from small-scale systems, where shaken bioreactors are commonly applied, is simple and has been successfully proven up to the cubic meter scale. However, orbitally shaken single-use reactors are only suitable for certain applications such as cultivating animal or plant cells with low oxygen demand. Thus, detailed knowledge about the performance of such systems on different scales is essential to exploit their full potential. This article presents an overview about opportunities and limitations of shaken single-use reactors.

Human primary cells (e.g. adult stem cells) as well as differentiated cells, including those of the immune system, have been found to be therapeutically useful and free of ethical concerns. Several products have received market authorization and numerous promising clinical trials are underway. We believe that such primary therapeutic cells will dominate the market for cell therapy applications for the foreseeable future. Consequently, production of such cellular products warrants attention and needs to be a fully controlled pharmaceutical process. Thus, where possible, such production should change from manufacture towards a truly scalable industrialized process for both allogeneic and autologous products. Here, we discuss manufacturing aspects of both autogeneic and allogeneic products, review the field, and provide historical context.

During the last few years virus like particles (VLPs) have become increasingly interesting for the production of vaccines. This development is explained by their excellent safety profile as well as a significant number of clinical studies showing strong and long-lasting protection. A further reason is the possibility of speeding up VLP vaccine manufacturing by implementing single-use (SU) technology in the case of mammalian and insect-cell-based processes, for which a multitude of SU devices up to middle-volume scale already exist. After briefly introducing the vaccine types and expression systems currently in use, this chapter turns to VLP vaccines and the insect cell/baculovirus expression vector system (IC/BEVS). Based on the main process characteristics and typical process flow of IC/BEVS-based VLP vaccine productions, suitable SU devices and their implementation are addressed. We subsequently report on the successful development of a fast, scalable benchtop production process generating a four-protein component influenza A H1N1 VLP vaccine candidate. This process is based on Spodoptera frugiperda (Sf)-9 cells and combines Redbiotec’s rePAX^TM technology with obtainable SU devices for upstream (USP) and downstream processing (DSP).

Microbial fermentations are of major importance in the field of biotechnology. The range of applications is rather extensive, for example, the production of vaccines, recombinant proteins, and plasmids. During the past decades single-use bioreactors have become widely accepted in the biopharmaceutical industry. This acceptance is due to the several advantages these bioreactors offer, such as reduced operational and investment costs. Although this technology is attractive for microbial applications, its usage is rarely found. The main limitations are a relatively low oxygen transfer rate and cooling capacity. The aim of this study was to examine a stirred single-use bioreactor for its microbial suitability. Therefore, the important process engineering parameters volumetric mass transfer coefficient (k _L a), mixing time, and the heat transfer coefficient were determined. Based on the k _L a characteristics a mathematical model was established that was used with the other process engineering parameters to create a control space. For a further verification of the control space for microbial suitability, Escherichia coli and Pichia pastoris high cell density fermentations were carried out. The achieved cell density for the E. coli fermentation was OD₆₀₀ = 175 (DCW = 60.8 g/L). For the P. pastoris cultivation a wet cell weight of 381 g/L was reached. The achieved cell densities were comparable to fermentations in stainless steel bioreactors. Furthermore, the expression of recombinant proteins with titers up to 9 g/L was guaranteed.

This chapter briefly reviews perfusion-based cultivation solutions used in biomanufacturing. It further introduces the innovative single-use Quorus Bioreactor, which was designed for the efficient cultivation of nontraditional production cell types. The Quorus Bioreactor design, process control, and productivity are described. Case studies are presented using Aspergillus niger and Lactococcus lactis as model organisms to demonstrate process flexibility, efficiency, and scalability.

As the age of the blockbuster drug recedes, the business model for the biopharmaceutical industry is evolving at an ever-increasing pace. The personalization of medicine, the emergence of biosimilars and biobetters, and the need to provide vaccines globally are just some of the factors forcing biomanufacturers to rethink how future manufacturing capability is implemented. One thing is clear: the traditional manufacturing strategy of constructing large-scale, purpose-built, capital-intensive facilities will no longer meet the industry’s emerging production and economic requirements. Therefore, the authors of this chapter describe the new approach for designing and implementing flexible production processes for monoclonal antibodies and focus on the points to consider as well as the lessons learned from past experience in engineering such systems. A conceptual integrated design is presented that can be used as a blueprint for next-generation biomanufacturing facilities. In addition, this chapter discusses the benefits of the new approach with respect to flexibility, cost, and schedule. The concept presented here can be applied to other biopharmaceutical manufacturing processes and facilities, including—but not limited to—vaccine manufacturing, multiproduct and/or multiprocess capability, clinical manufacturing, and so on.

Quality management systems are, as a rule, tightly defined systems that conserve existing processes and therefore guarantee compliance with quality standards. But maintaining quality also includes introducing new enhanced production methods and making use of the latest findings of bioscience. The advances in biotechnology and single-use manufacturing methods for producing new drugs especially impose new challenges on quality management, as quality standards have not yet been set. New methods to ensure patient safety have to be established, as it is insufficient to rely only on current rules. A concept of qualification, validation, and manufacturing procedures based on risk management needs to be established and realized in pharmaceutical production. The chapter starts with an introduction to the regulatory background of the manufacture of medicinal products. It then continues with key methods of risk management. Hazards associated with the production of medicinal products with single-use equipment are described with a focus on bioreactors, storage containers, and connecting devices. The hazards are subsequently evaluated and criteria for risk evaluation are presented. This chapter concludes with aspects of industrial application of quality risk management.