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Bioprocess Introduction

Lab Academy

Though bioprocessing is quite an ancient technique—beer has been brewed for several thousand years—modern biotechnology is still in its infancy. Bioprocess engineers make use of living cells and their components to produce many products for industrial use and bioprocesses are used to improve human living conditions. New applications such as stem cell cultivation may evolve to powerful tools in personalized medicine. There are lively debates about recent trends such as single-use equipment, automation, and perfusion culture. Scientists and engineers must keep track of these developments and consider associated issues, such as validation requirements, control strategies, and scale-up/scale-down approaches.

Heal, fuel, and feed the world

Bioprocess engineers produce many products for industrial use. Their applications are manifold, and the products can be found in the pharmaceutical, chemical, and nutrition industries. Stephen Sherwin, former chairman of BIO association put it aptly: “Heal, fuel, and feed the world”. [1]
The biological production process itself is usually referred to as upstream bioprocessing and comprises all workflow steps from cell banking, preculture, bioreactor inoculation, and main cultivation to final harvest. The following downstream steps, most often performed by a separate department, aim at purifying the product by separation, cell disruption, concentration, and other techniques.

Bioreactors – More than a tank!

Bioreactors have evolved from primitive fermentation vats in ancient times to modern stirred-tank bioreactors that conform to commonly agreed design standards. Mass and heat transfer, which are critical variables for the success of a biotechnological production process, are strongly influenced by the geometry of the bioreactor used. Gas transfer, mixing efficiency, nutrient supply, and heat transfer are all affected by the aspect ratio of the vessel, its impeller design , and the orientation and placement of baffles, feed tubes, and sensors within the bioreactor [2]. Engineering parameters such as the oxygen transfer rate (OTR) and the volumetric mass transfer coefficient (kLa) quantify the vessel’s efficiency. Since these factors have a direct impact on cell behavior and product titers (and thus on the overall success of the cultivation), it is no wonder that bioprocess engineers put considerable thought into the design, especially on larger production scales where limitations in mixing and homogeneity become obvious. Recent studies aim at better understanding these phenomena by using scale-down experiments.

Schematic overview of a bioreactor. Hi: Vessel height, Di: Vessel inner diameter, d: Impeller diameter, hVwmax: Filling height (maximum working volume)

Plastic. Fantastic? The rise of single-use bioreactors

Autoclavable glass bioreactors were traditionally used in laboratory-scale process development, as were stainless-steel tanks in manufacturing. During the last decade, however, single-use plastic bioreactors have been successfully established across biopharmaceutical production. Process development adopted bench-scale single-use solutions for cell culture, and lately also for microbial applications.
The advantages are obvious: Single-use bioreactors eliminate time- and labor-intensive cleaning and sterilization procedures and can thus shorten the time-to-market in a highly competitive business environment. There are still challenges to be overcome, such as concerns related to leachables and extractables and mass transfer limitations in large-scale single-use fermentors, but the technology is constantly improving and finding new proponents.

Control at the next level: Plan, execute, and analyze

Software capabilities are what sets a sophisticated bioreactor system apart. In bioprocess development, process engineers need control software that not only monitors and controls process parameters, but integrates planning, execution, tracking, and analysis of experiments. In this way, the software supports the implementation of Quality by Design (QbD) principles, ensuring product quality and accelerating scale-up.

DoE design space
Design of experiments (DoE) is a structured approach that investigates how critical process parameters interact and how they influence cell growth, titer or product quality. Easy-to-use DoE formats simplify process development efforts and documentation.

Online integration of autosamplers or analytical devices, such as mass spectrometry, Raman spectroscopy, nutrient analyzers, and HPLC permits deeper insight into the state of the culture, and allows for feedback control and automation.
A great deal of data is created in bioprocessing and its analysis can be time-consuming. Ready access to the data and the availability of easy-to-use tools for evaluation are key to a successful business.

What’s down the road? Trends in bioprocessing

Shortening time-to-market and overall reducing development costs remain the key profit drivers in the highly competitive biopharmaceutical and biotech industries. Decision makers in bioprocess laboratories seek to optimize costs per run, turn-around times, lab utilization, and titer gain.

With improved efficiency in industrial bioprocessing and higher titers, average bioreactor volumes in manufacturing are getting smaller [3]. Along with this trend goes the growing interest in continuous cultivation and perfusion technologies, which can achieve very high cell densities.
Personalized medicine is another exiting development that will dramatically expand bioprocess production. With commercialization ahead, more and more researchers working with embryonic, adult or induced stem cells are looking into establishing reproducible and validatable processes to cultivate their cells.
  1. BIOtechNOW. Our commitments to help heal, fuel and feed the world. Speech by Stephen Sherwin at BIO 2011. http://www.biotech-now.org/corporate/2011/06/our-commitments-to-help-heal-fuel-and-feed-the-world [cited January 4, 2017]
  2. Mandenius C-F (2016): Challenges for Bioreactor Design and Operation. In: Bioreactors. Design, Operation and Novel Applications. Weinheim, Germany
  3. Doig A, Jones SD (2016): Exciting Trends in Bioprocessing. White Paper by BioProcess Technology Consultants, Inc., Woburn, MA, USA