Ralf Pörtner

By Valentin Jossen, Ralf Pörtner, Stephan C. Kaiser, Matthias Kraume, Dieter Eibl and Regine Eibl

Part of the book: Cells and Biomaterials in Regenerative Medicine

By Johannes Möller and Ralf Pörtner

Production processes for biopharmaceuticals with mammalian cells have to provide a nearly optimal environment to promote cell growth and product formation. Design and operation of a bioreactor are complex tasks, not only with respect to reactor configuration and size but also with respect to the mode of operation. New concepts for the design and layout of process strategies are required to meet regulatory demands and to guarantee efficient, safe, and reproducible biopharmaceutical production. Key elements are critical process parameters (CPPs), which affect critical quality attributes (CQAs), quality by design (QbD), process analytical tools (PAT), and design of experiment (DoE). In this chapter, some fundamentals including process and control strategies as well as concepts for process development are discussed. Examples for novel model-based concepts for the design of experiments to identify suitable fed-batch-feeding strategies are shown.

Part of the book: New Insights into Cell Culture Technology

By Ralf Pörtner, Shreemanta K. Parida, Christiane Schaffer and Hans Hoffmeister

Immune cell therapies have been studied in numerous clinical trials using Advanced Therapy Medicinal Products (ATMP) against a number of diseases having no or inadequate alternative therapies available, for example, various cancer types, cerebral stroke, cardiac infarction, severe autoimmune disorders, or chronic infections. Despite the enormous number of positive observation in ex vivo or animal studies, convincing results in clinical studies remain scanty. The chapter presents a survey and reveals that the manufacturing of immune cells especially for clinical trials is until today primarily performed using archaic, scarcely controlled, and incomparable processes and methods. A deeper characterization of ex vivo expanded immune cells is urgently needed not only on the level of a few receptors and ligands on the cell surface but also with respect to the ever-contained subtypes in an expanded immune cell population, the pattern of secreted effector molecules, and their amounts over time and influences from in vivo components on them.

Part of the book: Stem Cells in Clinical Practice and Tissue Engineering

By Hao-Hsiang Hsu, Katharina Schimek, Uwe Marx and Ralf Pörtner

Characterization of native skin or cultured 3D skin models with respect to permeability plays an important role for the development and testing of pharmaceuticals and cosmetics. Extensive efforts have been dedicated to determining the key parameters describing permeability and diffusion. Whereas respective methods are well established for native skin biopsies, only few are available for 3D skin models, as these have usually much lower dimensions. In this chapter, some fundamentals about permeation and diffusion as well as state of the art of measurement methods used for skin biopsies are summarized. An alternative method for the determination of the permeation in a membrane insert system and the use of a modular simulation to support permeability studies is presented and discussed.

Part of the book: Biomaterials in Regenerative Medicine

By Cedric Schirmer, Thomas Nussbaumer, Reto Schöb, Ralf Pörtner, Regine Eibl and Dieter Eibl

Stirred tank bioreactors are still the predominant cultivation systems in large scale biopharmaceutical production. Today, several manufacturers provide both reusable and single-use systems, whereas the broad variety of designs and properties lead to deviations in biological performance. Although the methods for bioreactor characterization are well established, varying experimental conditions and procedures can result in significantly different outcomes. In order to guarantee a reliable comparison and evaluation of different single-use and reusable bioreactor types, standardized methods for their characterization are needed. Equally important is the biological capability of bioreactors, which must be accessed by standardized cultivation procedures of industrially relevant organisms (bacteria, yeasts as well as mammalian and animal cell cultures). In addition, the implementation of well-defined uniform procedures for biological and engineering characterization during the development phase can support a fast assessment of the suitability of a bioreactor system. Based on stirred bioreactors, we describe the aspects of the engineering characterization in order to discuss further the biological characterization as a valuable complement. Finally, a case study is presented.

Part of the book: Biopharmaceuticals

By Ralf Pörtner and Rebecca Faschian

Fixed-bed processes operated in perfusion, where cells are immobilized within macroporous carriers, are a promising alternative to processes with suspended microbial or mammalian cells. Their potential has been demonstrated for many purposes. Nevertheless, the number of industrial fixed-bed processes is quite small. To some extent, this is due to the lack of process development tools for fixed-bed processes. To fill this gap, a strategy was developed for the design and evaluation of relevant process parameters of fixed-bed processes. A scale-up concept is presented in order to evaluate the performance as part of process design of fixed-bed processes. This comprises fixed-bed reactors on three different scales, the smallest being the downscaled Multiferm with 10 mL fixed-bed units, the second a 100 mL fixed-bed reactor, and the third a pilot-scale reactor with 1 L fixed-bed volume. The performance of this concept will be discussed for fixed-bed cultures of lactic acid bacteria. Furthermore, a reaction kinetic model for the design of fixed-bed reactors will be presented.

Part of the book: Growing and Handling of Bacterial Cultures