Using glass vessel reactors as a comparison, the subs were evaluated in scaleup studies to determine the applicability of the disposable design. This chapter comprises engineering aspects of bioreactor systems design, operation, scale up developed or adapted for cultivation of mammalian cells, such as bioreactors for suspension culture stirredtank reactors, bubble columns, and airlift reactors, fixed bed and fluidized bed reactors, hollow fiber and membrane reactors, and, finally. Most production bioreactors have a vvm rate in the 0. Table 2 illustrates the pilot conditions necessary to model the 150,000l unit in table 1. The idea is to combine two individual bioreactors into a twocompartment. A new single use bioreactor for small scale cell cultures. A number of benchtop mini or micro bioreactors are available that incorporate sensors and use software to optimize conditions. Liquid mixing can also become important in larger bioreactors working. Scaling up bioreactors fluid dynamics by applying analytical techniques often reserved for largescale industrial bioreactors to smaller labbased counterparts, researchers. Since scale up principles for stirred bioreactors are generally better characterized than those for other bioreactor types, such as rockertype wave bioreactors gossain et al. Bioreactors play a key role in the field of biologics, where they are used for the production of recombinant therapeutic proteins by large scale cultivation of animal cells. Bioreactors classification and types biotech articles. An issue that has received mixed opinion, in scaling up of bioreactors, is whether to increase the size or the number of reactors when moving to industrial scale.
A partnership for scale up application note perfusion has emerged as a viable technology for the commercial production of biopharmaceuticals. It can also facilitate all control functions as a bioreactor more. Sep 30, 2014 yeast scaleup example production goal. For each reactor configuration,the appropriate process conditions depend on parameters such as the reactor scale,particle size distribution,slurry density,slurry viscosity,oxygen demand of the biomass, and the solids holdup kleijntjens, 1991. Ultimately, the concept of combining the activities of multiple. The smallscale bioreactor process examined was scaled up to 2000l scale, and it was found that with respect to cellculture performance, metabolite profiles, product titer, and product quality, both the singleuse bioreactors and the 5l glass vessels provided good smallscale models of.
Bioreactor scaleup and oxygen transfer rate in microbial. Use bioreactors by emily stoker, master of science utah state university, 2011 major professor. The small stirred tank has been important for scaleup, scaledown, strain optimization, characterization, and process development. If manual intervention is required, it should be correctly. There are several types of bioreactors, including stirredtank, airlift, hollowfiber, and rotary cell culture system rccs designs. Scaleup and basis of calculation mass balance class 05 duration. Cell culture scaleup in stirredtank singleuse bioreactors. Perfusion solutions can offer very costefficient scale up solutions, driving down. When making the transition from conventional dishbased cell culture to bioreactors, it can be less daunting to start with smaller vessels and scale up if needed, after conditions are optimized. Scale up and basis of calculation mass balance class 05 duration. Therefore, the design of bioreactors and the scale up of different.
Request pdf bioreactor scaleup scaleup is the process of. Table 1 lists common needs and expectations related to scale up of cell culture bioreactors that industryoriented bioengineers frequently mention. Scale up of aerobic fermentations is often carried out on the basis of a constant oxygen transfer coefficient. Bioreactors play a key role in the field of biologics, where they are used for the production of recombinant therapeutic proteins by largescale cultivation of animal cells. Scaling up bioreactors fluid dynamics by applying analytical techniques often reserved for largescale industrial bioreactors to. Equipment design considerations for large scale cell culture.
Scaleup for the growth of microorganisms is usually based on maintaining a constant dissolved oxygen concentration in the liquid broth, independent of reactor size. Thomas falkman, scientist, ge healthcare evaluating applications data is one way to learn about bioreactors and other technologies that support your complex bioreactor operations. Some scientists and engineers in biotech industry dedicate their entire careers scaling up various bioreactor processes, and each time they may encounter something new. Scaledown bioreactors have been applied in bioprocess development to study the response of microbial cell factories and other expression systems to various stressinducing concentration gradients.
The only practical way to scaleup volumes of mesenchymal stem cells mscs is by using microcarriers in singleuse bioreactors, say scientists from astar and instituto superior tecnico. The small scale bioreactor process examined was scaled up to 2000l scale, and it was found that with respect to cellculture performance, metabolite profiles, product titer, and product quality, both the singleuse bioreactors and the 5l glass vessels provided good small scale models of the large scale model. Scalingup stem cells with singleuse bioreactors and. Cfd analyses used in the design and scaleup of stirred tank.
This chapter comprises engineering aspects of bioreactor systems design, operation, scaleup developed or adapted for cultivation of mammalian cells, such as bioreactors for suspension culture stirredtank reactors, bubble columns, and airlift reactors, fixed bed and fluidized bed reactors, hollow fiber and membrane reactors, and, finally. The work demonstrated a great comparison and showed how versatile the wave 25 bioreactor is. Bioreactors scaleup microbial processes gasliquid interface in aerobic bioprocesses, oxygen is a key substrate. Scale up for the growth of microorganisms is usually based on maintaining a constant dissolved oxygen concentration in the liquid broth, independent of reactor size. Design and scaleup of production scale stirred tank fermentors.
Gluz bengurion university of the negev beersheva, israel key words bubble column fluid dynamics gas holdup heat transfer liquid. Typical applications range from smallscale protein expression to. Scale down bioreactors have been applied in bioprocess development to study the response of microbial cell factories and other expression systems to various stressinducing concentration gradients. Hollow fiber membrane bioreactors these reactors have hollow fibers are made from cellulose acetate, acrylic polymers, polysulphone etc. Scaleup of aerobic fermentations is often carried out on the basis of a constant oxygen transfer coefficient. Sartorius the univessel su is suitable for mammalian, insect and plant cell culture in scales up to two liters volume. This study shows a process for scaling up adherent vero cells from static cell factories to influenza production at 50 l scale using wave bioreactor systems and readytoprocess singleuse equipment. While it is desirable to keep as many operating parameters constant as possible during the scale up, the number of constant parameters realizable is limited by the degrees of freedom in designing the large scale operation. Due to the nature of these various parameters, it is not possible to maintain them all during scaleup under one set of conditions.
Integrated design of experiments doe for benchtop bioreactors role of doe and benchtop bioreactor systems integrated doe workflow case study. Scaleup and comparison studies evaluating disposable. Efficient scaleup of bioreactors for production of mammalian cells is a great challenge in. Equipment characterization to mitigate risks during transfers of cell. Often they blend these strategies and improvise a new strategy that serves. Bioreactor, cell culture, large scale, mass transfer, mixing, scale up, stirred tank full text the full text of this article is available as a pdf 3. Mscs are multipotent stromal cells that can differentiate into a variety of cell types which are being investigated for tissue engineering and cellular. Developing biopharmaceuticals or biological cell materials at. Scaleup analysis for a cho cell culture process in large. Scaling up and design of bioreactors scale up deals with transferring laboratory or pilot plant data to commercial production.
A number of benchtop mini or microbioreactors are available that incorporate sensors and use software to optimize conditions. They have an industrial rigidwall design for supporting scale. Scaling up your cell cultures to bioreactors biocompare. As another example, a multipronged approach can also be used to i demonstrate equivalent performance between traditional alloy and proposed singleuse equipment, ii validate cfd simulation, and iii extend performance projections to intermediate and fullscale equipment. Since scaleup principles for stirred bioreactors are generally better characterized than those for other bioreactor types, such as rockertype wave bioreactors gossain et al. Process scaleup between 3 different stirred tank bioreactors was studied. T1 scale up bioreactor design and culture optimization. Published case studies report the scalability of su systems from microto production scale bioreactors fernald et al. The fe rmentors, heat exchangers, evaporators, filters, and related equipment need scale up techniques for design and proper operation. However, to match fullscale u s, the pilot vvm may need to be more than 10. In addition, to simplify the manufacturing process and create a completely disposable environment for cell culture, disposable dissolved oxygen do probes and the fiber optic technology associated. This chapter comprises engineering aspects of bioreactor systems design, operation, scaleup developed or adapted for cultivation of mammalian cells, such as bioreactors for suspension culture.
As another example, a multipronged approach can also be used to i demonstrate equivalent performance between traditional alloy and proposed singleuse equipment, ii validate cfd simulation, and iii extend performance projections to intermediate and full scale equipment. In 1940s the large scale production of penicillin was a major breakthrough in biotechnology. Scale up is easy since several parallel fiber units can be added. It may also have an important role in the development of individualized medicine 2. Automated bioreactor system with commercial or modified multitray vessel to perform entire culturing process all in one closed system including filling, seeding, emptying, medium exchange, cell detachment, and harvesting. Design, characterization, and scaleup strategy for a new. Scaleup of processes based on su bioreactors animal cell. Scaleup considerations for monoclonal antibody production. The flexibility of smallscale singleuse bioreactor solutions. Scalingup and design of bioreactors scaleup deals with transferring laboratory or pilot plant data to commercial production. Some 20 years ago, the computer technology started to make advanced process control possible. Regardless what kind of production process a bioreactor or. Jul 14, 2014 when making the transition from conventional dishbased cell culture to bioreactors, it can be less daunting to start with smaller vessels and scale up if needed, after conditions are optimized. This gen webinar will first introduce and discuss the engineering concepts of the allegro str bioreactors, a square bioreactor design with volumes of 200 l.
Stirredtank su reactors combine the benefits of su systems with mixing principles found in traditional stainlesssteel reactors. Observations on scaleup yusuf chisti department of chemical engineering, university of waterloo, waterloo, ontario, canada n2l 3gl received 26 october 1992. Biological engineering this study was performed to increase knowledge of oxygen mass transfer k. Published case studies report the scalability of su systems from microto productionscale bioreactors fernald et al. In these reactors, the primary agitation criterion is gen erally the mass transfer capability. This chapter comprises engineering aspects of bioreactor systems design, operation, scale up developed or adapted for cultivation of mammalian cells, such as bioreactors for suspension culture.
Some scientists and engineers in biotech industry dedicate their entire careers scaling up various bioreactor processes. Challenges of scale down model for disposable bioreactors. Bioblu singleuse vessels have rigid walls to combine the best of both single and multiuse worlds. The development of genetic engineering have played a major role in. The fe rmentors, heat exchangers, evaporators, filters, and related equipment need scaleup techniques for design and proper operation. Combining equations 1 and 2 we obtain the following relation.
Table 1 lists common needs and expectations related to scaleup of cell culture bioreactors that industryoriented bioengineers frequently mention. T1 scaleupbioreactor design and culture optimization. Celltech decided to increase the size rather than the number of the bioreactor for production of monoclonal antibody from animal cells by designing a 10,000l bioreactor. Stirred tank bioreactors are the standard in the biotechnology industry and have been used for over 40 years 1. The oxygen transfer rate otr must be known, and if possible predicted to achieve an optimum design operation and scaleup of bioreactors. An issue that has received mixed opinion, in scalingup of bioreactors, is whether to increase the size or the number of reactors when moving to industrial scale. First, the most used measuring methods are revised. Scalingup a chemical process from lab to manufacturing only gives useful results with accurate heat transfer coefficients. Effective scaleup is essential for successful bioprocessing. Chapter 4 oxygen transfer in a production scale bioreactor. A bioreactor refers to any manufactured device or system that supports a biologically active environment. While it is desirable to keep as many operating parameters constant as possible during the scaleup, the number of constant parameters realizable is limited by the degrees of freedom in designing the largescale operation. Three factor full factorial doe minimizing risk by automation summary.
In one case, a bioreactor is a vessel in which a chemical process is carried out which involves organisms or biochemically active substances derived from such organisms. Advantages extracellular products can be separated from cells at the same time. Oct 27, 2017 this gen webinar will first introduce and discuss the engineering concepts of the allegro str bioreactors, a square bioreactor design with volumes of 200 l, l, and 2000 l, and then utilize. In bioreactors, enzymes created by microorganisms attack the plant. Using glass vessel reactors as a comparison, the subs were evaluated in scale up studies to determine the applicability of the disposable design. For each reactor configuration,the appropriate process conditions depend on parameters such as the reactor scale,particle size distribution,slurry density,slurry viscosity,oxygen demand of the biomass, and the solids hold up kleijntjens, 1991. Adherent and suspension bioreactors for viral vector manufacturing are evolving. Effective scale up is essential for successful bioprocessing. Improved scaleup strategies of bioreactors springerlink.
Process scale up between 3 different stirred tank bioreactors was studied. Scaleup and scaledown methodologies for bioreactors. Describes the stateoftheart techniques and methods involved in the design, operation, preparation and containment of bioreactor systems, taking into account the interrelated effects of variables associated with both upstream and downstream stages of the design process. Testing and simulation approaches for singleuse bioreactor. In cell culturebased vaccine production, scaleup of adherent cells is challenging. Scaleup of cell culture bioreactors using biomechatronic design. However, for each choice, a robust manufacturing process is critical to ensure it is scalable for these novel therapies to reach the patients. This chapter describes relevant aspects of industrialscale fermentation, an expanding area of. N2 tubular and the flat plate are the two most common general designs of microalgal photobioreactors.
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