about   CII home   shop   checkout
Conference Banner

Scaling Up & Down With Optimized Bioreactors + Disposables conference - Day 1

Archived Content

Scaling Up & Down with Optimized Bioreactors & Disposables 

Day 1 | Day 2 | Download Brochure | Short Courses 


6:00 - 9:00 pm Recommended Dinner Short Course* 

SC5 Connecting the Dots: Understanding Your Bioprocess Data 

*Separate registration required 


This meeting will explore the process development strategies and computational tools for scaling up protein production, including representative scale-down models. Optimizing bioreactor engineering and design will also be addressed, along with single-use technologies and monitoring /analyzing processes to ensure optimal conditions and productivity. Join in the discussion with international experts who will share their important, innovative work and case studies with the shared goal of manufacturing protein-based products.

8:00 am Registration and Morning Coffee



8:25 Chairperson’s Opening Remarks

Krist V. Gernaey, Ph.D., Associate Professor, Center for Process Engineering and Technology (PROCESS), Department of Chemical and Biochemical Engineering, Technical University of Denmark


What Scales Up Must Scale Down – Spinning Wheels?

Beth-JunkerBeth Junker, Ph.D., Senior Scientific Director, BioProcess Development, Merck Research Laboratories - Biography 

Scale-down models have been and remain essential to process development, process performance qualification, and troubleshooting of scaled-up process operations. Practicality dictates that most process development experiments are conducted at the small scale.  However, scale-down model fidelity varies considerably for different bioprocess steps, expression systems, and protein products.  This talk presents the current state of scale-down models, offers an explanation about why this state exists despite decades of scale-up experience, and what advances need to be undertaken to "let the spinning wheel fly".


From Micro to Small Scale Fermentation – Combining Cell Line and Process Development

René-BrechtRené Brecht, Ph.D., Vice President, Process Science & Manufacturing, ProBioGen AG - Biography 

The development of new cell lines and cell culture processes has to fulfill the demand for high productivity, shortened timelines and robustness. Therefore, effective screening of clones has to be combined with process optimisation work early on. Micro and small scale bioreactors covering a range from a few millilitres up to ten litres are used and need to be understood in terms of transferability of parameters to the next scale. Different case studies are presented to illustrate the strategies we employ. 

9:30 Consistent Fed-Batch Bioprocess Development in the µL to L-Scale

Stefan JunneStefan Junne, Ph.D., Group Leader, Process and Systems Biotechnology, Chair, Bioprocess Engineering, Institute of Biotechnology, Technische Universität Berlin - Biography 

From concept to market, it typically takes from 5 to 10 years for the development of biotechnological processes. The step from bench-scale to pilot- and production-scale is crucial, since multidisciplinary approaches are necessary to circumvent typical problems of the scale-up process. One factor causing issues is the inconsistency of the process mode. Therefore, we have developed in situ susbtrate delivery systems, which allow a fed-batch procedure in any scale. In combination with state-of-the-art experimental design approaches, a fast and consistent process development in well-plates on liquid-handling systems becomes possible. Therefore, also microsensor integration and scale-down reactor concepts in the L-scale are considered.

10:00 Coffee Break in the Exhibit Hall with Poster Viewing



10:45 Qualification and Application of a Bioreactor Scale-Down Model for a Microcarrier Perfusion Cell Culture Process

Caroline DiCesare, Process Engineer 1, Commercial Cell Culture Development, Genzyme Corp.

One of the current manufacturing challenges for cell culture processes that were developed decades ago is the ability to improve process robustness and troubleshoot problems.  To overcome this challenge, a qualified scale-down model is crucial in order to conduct studies that can be translated to the larger scales.  For this purpose, a cell culture scale-down model using 12-liter bioreactors was developed and subsequently qualified for a microcarrier-based perfusion cell culture process.  For qualification, statistical equivalency needs to be established by comparing selected process performance parameters in the 12L scale to the large scale using a two one-sided test (TOST) analysis. The results showed that cell culture performance and product quality attributes were within the specification range in the scale down model.  The qualified model can be used for example to evaluate new cell bank candidates for future implementation in manufacturing, to analyze the effect of media additives on cell culture performance, and for continuous improvement support.

11:15 Computational Methods Supporting Process Intensification

Ulrich Krühne, Ph.D., Senior Researcher, Center for Process Engineering and Technology (PROCESS), Department of Chemical and Biochemical Engineering, Technical University of Denmark

The talk presents a number of case studies, where computational methods have been used for gaining a more detailed understanding of complex interactions in biochemical applications. The cases will comprise scenarios across scales reaching from microfluidic examples to pilot plant scale setups. Computational fluid dynamic (CFD) models coupled with biological models will be presented for shedding light on reactor design, determination of material properties and optimization routines.


Integrating and Utilizing Computational Fluid Dynamics in the Cell Culture Scale Up Work Flow

Toby Blackburn, Engineer, Technical & Cell Culture Development, Biogen Idec, Inc.

As part of an effort to further understand scale up considerations and assumptions, computational fluid dynamics models were developed for all bioreactors at all scales at Biogen Idec. Various methods of model standardization and validation were discussed. The final approach involved utilizing fluid mixing characteristics, including Np, Kolmogorov mixing length and turbulent energy dissipation rate, as an independent tool in conjunction with experimental mix time and mass transfer to minimize impact to cell culture processes upon scale up. CFD simulations were run for all reactors across the operational range, but at RPMs fixed across the scales by P/V. Initially this P/V was calculated using a “book value” power number. Throughout the course of the data analysis, this power number appeared to overestimate system efficiency in dual impeller cases, leading to a revision in scale up approach when transferring between single and dual impeller systems.

12:00pm Luncheon Presentation (Sponsorship Opportunity Available) or Lunch on Your Own



1:55 Chairperson’s Remarks

Stefan Junne, Ph.D., Group Leader, Process and Systems Biotechnology, Chair, Bioprocess Engineering, Institute of Biotechnology, Technische Universität Berlin

2:00 Bioreactor Scaling Up and Down: How to Perform Successful Process Development

Aurore-LahilleAurore Lahille, Ph.D., Specialist, New Technologies and Manufacturing Support, Merck Serono - Biography 

Manufacturing planning depends on performances derived from process development data. This presentation will provide guidelines to reach a successful bioreactor process scale-up and down. My talk will span either disposable or reusable small process development bioreactors (15mL to 3L) to more than 1000L bioreactor, illustrating Merck’s biodevelopment way forward.


2:30 Topology Optimized Bioreactors — A Design Example with Immobilized Yeast

Krist-GernaeyKrist V. Gernaey, Ph.D., Associate Professor, Center for Process Engineering and Technology (PROCESS), Department of Chemical and Biochemical Engineering, Technical University of Denmark - Biography 

This work exploits the increased design flexibility offered by microsystems for optimizing the operation of a microbioreactor. In this optimization project, the production of a recombinant protein in a continuous culture of immobilized Saccharomyces cerevisiae was used as a case study. A topology optimization methodology was applied to a mathematical model of the S. cerevisiae microbioreactor, in order to obtain the spatial distribution of immobilized yeast that maximizes protein concentration at the outlet. Compared to a stirred tank reactor, productivity improvements of up to a factor ten were predicted.

3:00 Insights into Large-Scale Bioreactors

Andreas Lübbert, Ph.D., Professor, Center for Bioprocess Engineering, Institute of Biochemistry and Biotechnology, Martin-Luther-University

In recent years we learned much about the transport properties of large bioreactors. Here we discuss the most important aspects, for instance, the improvements in our understanding of the oxygen mass transfer in stirred tank bioreactors, the problem of CO2 accumulation in large-scale cell culture bioreactors and its solution. We will focus on the mechanistic understanding of the effects and the validation of the corresponding engineering models by means of physical measurements.

3:30 Refreshment Break in the Exhibit Hall with Poster Viewing

4:15 Enhancing Infrastructure Flexibility – Design of a Novel Automated Methanol Feed System for Pilot-Scale Fermentation of Pichia pastoris

Kristie-ApgarKristie R. Apgar, Research Chemical Engineer, Bioprocess Clinical Manufacturing Technology, Merck Research Labs, Merck & Co., Inc. - Biography 

Industrial fermentation of Pichia pastoris requires a large volume of methanol feed during the induction phase.  However, a large volume methanol feed is difficult to employ in the processing suite due to the inconvenience of constant monitoring, manual manipulation steps, and fire and explosion hazards.  To optimize and improve safety of the methanol feed process, a novel automated methanol feed system has been designed and implemented for industrial fermentation of P. pastoris.  Details of the design of the methanol feed system are described.  The main goal of the design was to automate the methanol feed process and to minimize the hazardous risks associated with storing and handling large quantities of methanol in the processing suite.  The methanol feed system is composed of two main components: a Bulk Feed system and up to three portable Process Feed systems.  The Bulk Feed system automatically delivers methanol from a central location to the portable Process Feed system.  The Process Feed system provides precise flow control of linear, step or exponential feed of methanol to the fermenter.  Large-scale fermentations with linear and exponential methanol feeds were conducted using two Mut+ (methanol utilization plus) strains, one expressing a recombinant therapeutic protein and the other a monoclonal antibody.  Results show that the methanol feed system is accurate, safe, and efficient.  The feed rates for both linear and exponential feed methods were within ± 5% of the set points and the total amount of methanol fed were within 1% of the targeted volume. 

4:45 Scaling-Down a Process: Lessons in Correcting Your Assumptions in Order to Create a Small Scale Bioreactor Model

E. Todd SorensenE. Todd Sorensen, M.S., Development Associate 4, Alexion Pharmaceuticals, Inc. - Biography 

The need for robust, reproducible large-scale cell culture bioreactor performance for the production of recombinant proteins and monoclonal antibodies led us to develop reliably predictable small-scale bioreactor models.  During the exercise of creating a small-scale bioreactor model for our 10,000L Bioreactors, not only did we discover how to operate our bioreactors, we also learned that several of our initial assumptions were incorrect.  Our approach started by defining requirements for our model such as retaining product quality attributes across scales and matching trends in growth and productivity.  Next, we employed computational fluid dynamics (CFD) software in conjunction with a series of experiments to characterize each scale, focusing on: magnitude of shear forces, mixing time, bubble size distribution and liquid addition dispersion.  We explored the impact of modifying a host of operating conditions including: agitation rate, pH setpoint, dissolved oxygen setpoint, sparge rate, location of liquid additions (i.e. feed and alkaline solution) and timing of liquid additions.  Ultimately, we engineered our model to go from outperforming the large-scale by nearly 50% in terms of productivity to closely matching final titer while preserving product quality.  We will discuss the lessons learned by going through this process.

5:15 Networking Reception, Last Chance for Exhibit and Poster Viewing

6:45 End of Day

Day 1 | Day 2 | Download Brochure | Short Courses 

Download Conference & Course Catalog

CHI Catalog March 2018 - August 2018 Cover