Cell line stability is another factor that should be considered since volumetric and specific productivity decline as cell age increases for. Nov 29, 2016 fed batch culture is currently the most common industrial process for cho cell culture. In a fedbatch process, a basal medium supports initial growth and production, and a feed medium prevents depletion of nutrients and sustains the production phase 9. Selection of chemically defined media for cho cell fedbatch. For a fed batch process volumetric productivity and product titer are important outputs.
An economic comparison of three cell culture techniques. These systems represent the best tool for optimization of your batch, fed batch, or continuous cell culture processes using suspended cells or microcarriers. In order to better understand how design of experiments works as part of an optimization process for livecell antibody production, we can recreate the tasks. In this study, we describe a new blending design for the medium development of a fedbatch cell culture process, enabling the optimization of all medium components of a proprietary medium in one single experiment. Metabolic control in mammalian fedbatch cell cultures for. Designing feed strategies for fedbatch cho cultures. Article automated dynamic fed batch process and media optimization for high productivity cell culture process development franklin lu,1 poh choo toh,2 iain burnett,1 feng li,1 terry hudson,1. The 12 different fedbatch designs were developed and approved as optimal solutions for a. Effects of feeding strategy on cho cell performance in fed. Biocell pilot series bioreactors 60 l to 300 l dci. Rapid optimization of fedbatch processes using the micromatrix.
To achieve the highest performing cell culture, a fed batch culture strategy is frequently used. Optimization is key to achieving a highproducing cho cell culture. This was done automatically through the micromatrix software and required. Utilizing its expertise in process vessel manufacturing, cell culture and automated systems, dcibiolafitte introduces its biocell pilot series, a new generation of sip cip pilot bioreactor. Software to increase throughput and quality in cell line and.
General attempts to model fed batch processes have been described for an overview see. In the perfusion batch culture, the addition of the culture and withdrawal of an equal volume of used cell free medium is performed. Sep 18, 2019 impact of dynamic online fedbatch strategies on metabolism, productivity and nglycosylation quality in cho cell cultures. Developing an automatically controlled feeding process in an. Sep 14, 2017 designing a successful process to produce a particular biologic depends not only on fitting together the right cell culture media, cell line, and bioreactor, but also on careful control and. Doe to accelerate the optimization of fedbatch strategies 21. Cell culture process development on chos cells was initially conducted with cho cd efficientfeed a efa, efb, and efc. Cell culture process development for fedbatch using a novel. The use of a microbioreactor platform as cell culture process. Dynamic optimization of hybridoma growth in a fedbatch. Experimental evaluation in two independent fed batch cultures resulted in a. While the description of product concentration in the cell mass is rather. Jan 23, 2007 hybridoma 8f producing antif monoclonal antibodies mab were grown in batch and fed batch mode with glutamine as the limiting substrate. Optimization of process conditions for mammalian fedbatch.
An igg1producing cho cell line was cultured in hyclone. In the fedbatch process, we fed the culture starting on day 3 with cd efficientfeed c agt nutrient supplement thermo fisher scientific at 3% of the working volume per day. Statistical methods in media optimization for batch and fedbatch animal cell culture article in bioprocess and biosystems engineering 302. Nov 22, 2011 initial experiments were performed using chemically defined culture medium in 125 ml shake flasks with 50 ml working volume.
Apr 14, 2010 to date, typical production cell line specific productivities range from 20 pgcellday to 70 pgcellday and peak viability cell densities from 530. Optimization of bioreactor growth conditions and feeding strategy has the potential for several fold increase in heparosan yield, as a fedbatch process provides a feed medium that prevents depletion of nutrients and sustains the production phase 34. In the case of fed batch culture, the concentrated components of the nutrient are gradually added to the batch culture. Jiang and others published fedbatch cell culture process optimization. Based on these modeling approaches, optimization of fed batch processes has been attempted using pontryagins maximum principle 2, 3, greens theorem, or dynamic programming.
These approaches are rather complex, and they did not find their way in. Elevated pco2 affects the lactate metabolic shift in cho cell. Genedata bioprocess makes the development of new or optimized fedbatch and perfusion upstream processes more efficient by supporting all workflows. This approach increased inoculation cell densities and decreased cultivation times by. Modelassisted design of process strategies for cell culture. In the table the fedbatch operation is divided into two basic models, one without feedback control and the other with feedback control. Cell culture processes for monoclonal antibody production. These outputs are a function of viable cell density vcd, specific productivity q p, and culture longevity, which in turn are influenced by the medium and feed. Designing a successful process to produce a particular biologic depends not only on fitting together the right cell culture media, cell line, and bioreactor, but also on careful control and. Employing the cumulative cell hour concept, external metabolic flux.
For the production of mabs, high performing fed batch processes have. Fedbatch is an easy and popular way to intensify cell cultivations. Basal medium, feed medium, and process parameter settings are the three major factors for fed batch cell culture process optimization. Dec 01, 2009 each culture was run in a day fedbatch process with ph, do, and glucose control. Nov 30, 2017 the aim of this study was to investigate the effects of elevated pco 2 concentrations on the lactate metabolic shift phenomena in cho cell culture processes. How to optimize cell culture media to speed biopharma. Cell culture bioreactors microbial bioreactors software apps for bioreactors. Versatile modeling and optimization of fed batch processes for the. We automated that feed using eppendorfs biocommand batch control supervisory control and data acquisition scada software. Improvement and simplification of fedbatch bioprocesses with. Developing a feeding strategy a comprehensive process is required when developing a feeding strategy. Fed batch culture is, in the broadest sense, defined as an operational technique in biotechnological processes where one or more nutrients substrates are fed supplied to the bioreactor during cultivation and in which the product s remain in the bioreactor until the end of the run. During cell culture process development, the main goal is to achieve high titers and a defined product quality of the recombinant molecule. For subsequent projects involving chok1sv, fmte was added to efb or efc to help improve cell culture performance.
The design and optimization of a fermentation process plays a key role in achieving high productivity and robustness at the production scale. In this article, we discuss a strategy to improve operational procedures in an escherichia coli fed batch fermentation through automated process control. This work demonstrates the development of a fed batch process for a chinese hamster ovary cho cell line producing a monoclonal antibody mab. How to optimize cell culture media to speed biopharma development. This means that the fed nutrients must be supplemented in the right ratios and in sufficient amounts. Cell culture optimization would be so much easier if a universal feed existed. This process optimization toolbox will increase the titer of your cellcacho production cell line by saving 2 weeks of turnaround time, since the doe. I ended the conversation by asking andreas if he had anything else to add for listeners.
Fedbatch cell culture process optimization bioprocess. The ability to simultaneously test all media components presents the advantage that no potentially critical factors are missed. The 12 different fed batch designs were developed and approved as optimal solutions for a variety of different cellcacho production cell lines. Mar 25, 2018 mathematical model as key for process design. Performance can be improved by upgrading one or more of those three elements.
Cellretention systems add a level of complexity to the process. Comparing culture methods in monoclonal antibody production. In this publication, we show that at elevated pco 2 in batch and fed. The culture broth is harvested usually only at the end of the operational period. In the batch culture, the microorganisms are inoculated in fixed volume of medium. Fedbatch biofuel production process using a new brunswick. The ambr15 and modde software used here provided a path to obtain effective media formulations for a given specific cho cell line. Blends were tested on both the cell expansion and the fedbatch production phases, ensuring that. Modelling batch and fedbatch mammalian cell cultures for. Medium and feed optimization for fedbatch production of a.
This can be achieved through cell line engineering, media optimization and bioprocess development huang et al. He said that when optimizing fed batch culture, the manufacturing process should be kept in mind at all times. Optimization of hek293 cell culture in a new brunswick celligen. Modelling batch and fedbatch mammalian cell cultures for optimizing mab productivity by penny dorka a thesis presented to the university of waterloo in fulfillment of the thesis requirement for the degree of master of applied science in chemical engineering waterloo, ontario, canada, 2007 penny dorka 2007. Fedbatch operation an overview sciencedirect topics. A fedbatch operation is that operation in which one or more nutrients are added continuously or intermittently to the initial medium after the start of cultivation or from the halfway point through the batch process. The media mixture layout we designed using designexpert software. Optimization of fedbatch processes for two recombinant mammalian cell lines was carried out using simple ga. Automated dynamic fedbatch process and media optimization. Media optimization for cho fedbatch processes using a doe. The cell densities achieved in perfusion culture 30100 x 10 6 cellsml are typically higher than for fedbatch modes 525 x 10 6 cellsml.
An alternative description of the method is that of a. So we required a combined optimization of basal and feed media to fulfill our objective. Use the analysis wizard to model the three responses. We here demonstrate a novel feeding strategy which is designed to hold a particular metabolic state in a fedbatch process by adaptive feeding in. Towards the development of automated fedbatch cell culture. Fourteen process parameters were optimized medium and feed components and physical parameters. Media blending following a custommade mixture doe resulted in 376 different blends which were evaluated in 96dwp for cell culture performance in fed batch. Actipro cell culture production medium is intended to be used in combination with cell boost 7a and 7b supplements to enhance recombinant protein production in fed batch or perfusion processes.
Basal medium, feed medium, and process parameter settings are the three major factors for fedbatch cell culture process optimization. Details of fedbatch operation are summarized in table 1. The main goal of the study was to test the feasibility of the ga approach and not to optimize the particular processes as such. Mammalian cell culture process development clone evaluation media development process optimization screen and select the highest producing and most stable clone develop optimal growth and production media for each cell line optimize conditions for biomanufacturing process in a scaledown version scale up system. In its absence, says bd, try a feed that works across multiple base media and cells in a platform process. Cell culture media are complex entities that encompass large quantities of raw materials as well as a high level of. Applying this highthroughput method on a fed batch, rather than on a simple batch, process opens new perspectives for medium and feed development that enables identification of an optimized process in a short time frame. Here we discuss a rationally integrated approach that best serves the practices of fedbatch cell culture process optimization. Monoclonal antibody production was identified as being partially growth associated. A highthroughput media design approach for high performance. Automated dynamic fedbatch process and media optimization for.
The modelling of cell culture processes has gained increasing importance in the last decades because it can be applied to design, optimize and control production processes. May 01, 20 in this study, we describe a new blending design for the medium development of a fed batch cell culture process, enabling the optimization of all medium components of a proprietary medium in one single experiment. Modeling of the fed batch process and optimization of qp was used to. Finally, a multivariate analysis enabled identification of individual potential critical components for further optimization.
We recognize that all bioprocess systems are unique. High throughput automated micro bioreactor for high density fed batch strain selection ambr 15 fermentation is a high throughput automated bioreactor system for 24 parallel microbial fermentations in a costeffective 8 12 ml micro bioreactor format. Optimize fedbatch culture early in process development to save time and resources. Highthroughput media blending method for the medium development of a fed batch cell culture process. Automated dynamic fedbatch process and media optimization for high productivity cell culture process. The ultimate goal of this study is to establish a comprehensive dynamic model which may be used for modelbased optimization of the cell culture for mab production in both batch and fed batch systems. Versatile modeling and optimization of fed batch processes.
Automated dynamic fed batch process and media optimization for high productivity cell culture process development franklin lu,1 poh choo toh,2 iain burnett,1 feng li,1 terry hudson,1 ashraf amanullah,1 jincai li1 1oceanside pharma technical development, genentech, inc. Sixteen media formulations were designed from 43 of 47 components. A road map for efficient fedbatch cell culture optimization. Maintaining good culture for cells is very important in the last phase of the culture for this reason. Statistical methods in media optimization for batch and fed. Optimized cell culture media vital to process development. A robust base medium must first be identified and proven in small spinners or shaker cultures. Create a modde project and reproduce the experimental design that was used. Besides the fact that cell culture processes would simply not exist without cell culture media, the medium and associated feeds for fed batch processes represent a large portion of the cost of a biopharmaceutical process. Gibco bioproduction services utilizes a custom design of experiment doe approach which leverages a variety of high throughput tools such as simcell and clonepix to accelerate process and cell line development.
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