Biomedical Engineering and Bioengineering Commons^™

Moving From A Bioreactor Scale-Up/Scale-Down Approach To A More Holistic Operational Design Space View, Gene Schaefer, Rick Yeager, Ted Deloggio

Cell Culture Engineering XV

Scale-up of bioreactor processes for biologic products has been an area of focus in the industry for over 50 years and the results have generally been successful through the application of a number of specific correlations across scales for mass transfer, mixing, etc. However, the ability to visualize and understand the bioreactor design space in terms of these parameters has generally been limited as has any general understanding of how close a given process comes to certain sensitivity limits at various scales. As part of a project which involved establishing scale-down models at two different sites with long-term objectives of …

Process Optimization For Semi-Continuous Virus Production At High Cell Densities, Daniel Vazquez

Cell Culture Engineering XV

Background. Unlike production of recombinant proteins, continuous production of viral vaccines at high cell densities (HCD) is still constrained by host cell lysis during virus propagation and limited virus recovery from culture broth. Nevertheless, advanced fed-batch [1] and perfusion strategies can be applied to achieve a high-yield virus production processes. In this study, the development of a high-yield semi-continuous process for the production and purification of the modified vaccinia Ankara virus isolate MVA-CR19 and influenza A/PR/8 in HCD cultivations of the suspension cell line AGE1.CR.pIX (ProBioGen AG, Berlin) is presented.

Methods. Depending on the required scale, high cell …

Overcoming Scale-Up Challenges With A Non-Robust Cell Line, Sigma Mostafa, Brian Baker, Abhinav Shukla

Cell Culture Engineering XV

Cell culture scale up success depends on robust cell line, process, and equipment. Mixing characteristics of bench scale through large scale bioreactors need to be well understood and a reliable scale up parameter needs to be used. The cell culture raw material lot to lot variability as well as hydration protocol reliability needs to be considered. The cell culture process parameter ranges need to be broad enough to account for system variability and the process should not run at the edge of failure. In our experience, greater than 95% of cell lines are robust and easily scalable. Cell line robustness …

A Holistic Approach To The Scale-Up Of A Microcarrier-Based Perfusion Cell Culture Process For The Production Of A Therapeutic Enzyme, Jin Yin

Cell Culture Engineering XV

This case study describes our holistic approach of scaling up a microcarrier-based perfusion cell culture process for the production of a therapeutic enzyme directly from a 12L benchtop glass bioreactor to a commercial scale stainless steel bioreactor. Besides conventional scale-up challenges such as mixing, shear stress and mass transfer, the scale-up of this microcarrier-based cell culture process posed its own challenges, e.g. the original design of the commercial scale stainless steel bioreactor had difficulty suspending microcarriers. Additional challenges included achieving effective cell attachment after seeding, balancing microcarrier stratification and culture turbulence, and minimizing bubble shear stress and foaming. To mitigate …

Challenges In The Use Of Scale-Down Models For Understanding And Mitigating Process Variations Of A Monoclonal Antibody Production Process, Peter Russo

Cell Culture Engineering XV

Scale-down models are commonly used to execute process characterization studies, as well as to screen raw materials and to conduct investigations in support of manufacturing operations. During the clinical manufacture of a monoclonal antibody, consistent product quality was maintained; however, large variations in bioreactor harvest titer (> 2X) were observed between lots. Root cause analysis of this variation did not establish a linkage between culture performance and manufacturing execution or deviations. Further, small scale satellite reactor performance displayed lesser variability; thereby eliminating seed train and raw materials as potential root causes. Small scale investigations, using multiple scale-down models, were not …

Scale-Up And Scale-Down Topics Facing The Industry, Markus Michael Muller

Cell Culture Engineering XV

Scale-up and scale-down is bringing several challenges along. We present some recent examples where these challenges occur and how extensive hardware characterization by for example computational fluid dynamics has leads to get a better understanding of the processes themselves.

The increasing implementation of small scale bioreactor systems like ambr15 and ambr250 as well as the usage of new single use bioreactors (>2-L) in parallel to established glass vessels has led to additional challenges in scale-up and scale-down. The mini-bioreactor systems, originally used for screening approaches, are going to be implemented as small scale testing systems but could also be …

Process Optimization For Semi-Continuous Virus Production At High Cell Densities, Daniel Vazquez, Michael Pieler, Yvonne Genzel, Ingo Jordan, Volker Sandig, Udo Reichl

Cell Culture Engineering XV

Background. Unlike production of recombinant proteins, continuous production of viral vaccines at high cell densities (HCD) is still constrained by host cell lysis during virus propagation and limited virus recovery from culture broth. Nevertheless, advanced fed-batch [1] and perfusion strategies can be applied to achieve a high-yield virus production processes. In this study, the development of a high-yield semi-continuous process for the production and purification of the modified vaccinia Ankara virus isolate MVA-CR19 and influenza A/PR/8 in HCD cultivations of the suspension cell line AGE1.CR.pIX (ProBioGen AG, Berlin) is presented.

Methods. Depending on the required scale, high cell …