Those who take a systematic approach will be rewarded with a consistent large scale fermentation that meets performance expectations and enables good downstream performance as well. Scalingup of highcelldensity fermentation hcdf of pichia pastoris from the lab or pilot scale to the demonstration scale possesses great significance because the latter is the final. Lab performance plant performance plant target scale down protocol. The preservation of highyielding strains of microorganisms for fermentation is very. Best practices for successful scale up of industrial. Scaleup approach for fermentation process of production of. Production of organic acids, titratable acidity and phdevelopment during fermentation of cereal flours peter sahlin and baboo m. Recognition of and attention to scale dependent fermentation parameters is fundamental to reducingeven eliminating fermentation as a scale up risk. Increase in scale means an increase in volume and the problems of process scale up are due to the different ways in which process parameters are affected by the size of the. With the tremendous diversity of organisms and products in industrial fermentation, a precise and onesizefitsall strategy for scale up is not.
We also present a comprehensive description the fermentation product impurities, of microorganisms, chemical reactions, separation techniques, bioreactor types, fermentation conditions, gas liquid mass transfer, current industry status, process scaleup. Manual of industrial microbiology and biotechnology, 3 rd edition. A fermentationdefoaming tandem system was developed to resolve the problems of foaming and medium overflow during scaleup. We possess both the stateoftheart facilities and the most experienced technicians. In order to scale up production, pathway gene expression needs to be optimized to minimize metabolic bottlenecks and unwanted side products 109111.
Scaleup approach for fermentation process of production. A fermentation defoaming tandem system was developed to resolve the problems of foaming and medium overflow during scale up. Pfizer manufactured other antibiotics, notably terramycin, and vitamins using deeptank fermentation techniques. A unique requirement for commercial biopharmaceutical process scale up is process validation. We try to build industrial size fermenters capable or close of producing the fermentation products as efficient as produced in small. The problem of designing a fermentation process that balances the oxygen demand of the organism with the oxygen supply capacity of the fermenter is addressed. Culture medium optimization and scale up for microbial. Key factors for bioprocess technology selection, scale up and engineering of new facilities biocatalyst raw materials process technologies products scale economics s cale e conomics b. Let us simplify the similarities and differences between these two phrases in fermentation technology. In large fermentors, oxygen can be depleted in some area of the reactor 19. Brewing and foodbased fermentations were the beginnings of the fermentation industry as we know it today. Finally, the approaches to the scaleup and scaledown of fermentations are explored. Mechanical and aerospace engineering in the biopharmaceutical industry, fermentation is extremely important in pharmaceutical development, and in microbial research. This chapter covers a broad scope of issues related to microbial fermentation process scaleup and describes specific steps to plan and execute a scaleup project.
Fermentation, scale up, pilot plant scale, scale down. Scaleupscaledown techniques are vital for successful and safe commercialscale bioprocess design and operation. Fermentation performance at commercial scale equivalent to demonstration scale low variability in fermentation performance indicates process robustness and predictability top 5 commercial scale fermentations indicate continuous improvement opportunity consistent scale up to commercial,000l demonstration scale commercial scale 50x scale up. Principles of fermentation technology sciencedirect. Variables to be considered when changing fermentation scale implementing a scaling activity summary references and f. Different rhamnolipids had different performances in interfacial tension. For these objectives, scale up of cell cultures are essential and large scale fermentors of up to 10,000 liters are used for this purpose. In scale up of bioreactors mixing time is often used as criteria. Organism response under scale down protocol identical to large scale conditions. Optimization and scale up of industrial fermentation.
The traditional seed train includes thawing a vial and inoculating into shaker flasks for a certain number of stages. Optimization and scale up of industrial fermentation processes. Types and stages of fermentation process explained. Design and scale up of production scale stirred tank fermentors by ryan z. A brief account of the four stages of fermentation is given below. Penicillin production through deeptank fermentation. Upstream processing includes formulation of the fermentation medium, sterilisation of air, fermentation medium and the fermenter, inoculum preparation and inoculation of the medium. And start fermentation scale down by modeling the large. Contaminants may pose a competitive threat, consuming feedstock. This scale up procedure has been applied 11 to the data of rogovin et al.
Optimzing scaleup fermentation processes request pdf. It is important to understand that the process of scalingup a fermentation system is frequently governed by a number of important engineering. The optimization of the fermentation process is included in the strategic analysis of the viability of a project. At the turn of the twentieth century, fermentations were used to make chemicals such as glycerol for the manufacture of explosives. Scale up means increasing the scale of a fermentation, for example from the laboratory scale to the pilot plant scale or from the pilot plant scale to the production scale. However, as fermentation facilities usually are not strictly designed according to scale up criteria and the process conditions in the culture vessels thus may differ significantly and since any strategy and model can only insufficiently consider and reflect the highly complex interdependence and mutual interaction of fermentation parameters. Pdf optimizing scaleup fermentation processes sujitha. Presented at the annual meeting of the american institute of chemical engineers, salt lake city, utah, november 8, 2007. Consider the scale up of a fermentation from 10l to 0l vessel. Large scale fermentation manufacturing services for the. This chapter describes relevant aspects of industrialscale fermentation, an expanding area. Even though the number of publications on this topic in the field of gas fermentation is limited, many of the approaches developed through the metabolic engineering of e. Existing fermentation scale up methods cannot meet adequately the technical and economic demands of the modern biotechnology industry.
Driving innovation through bioengineering solutions. Jan 21, 2016 scaling up of highcelldensity fermentation hcdf of pichia pastoris from the lab or pilot scale to the demonstration scale possesses great significance because the latter is the final. Scale down model closely predicted scale up performance. Any industrial fermentation operation can be broken down into t hree main stages, viz, upstream processing, the fermentation process and downstream processing. Scale up approach for fermentation process of production of bacillus thuringiensis var kenyae based biopesticide r g muley, s sarkar, b l bhan, arunkumar,m narayanan and s r aik rescarch and development, hinuustan antibi otics limited, pi mpri. For some years, new methodologies have advanced with new production processes, allowing scaleup production and market introduction. Scribd is the worlds largest social reading and publishing site.
Design and scaleup of production scale stirred tank fermentors by ryan z. Scale up studies scale up studies are studies carried out at the laboratory or even pilot plant scale fermenters to yield data that could be used to extrapolate and build the large scale. This article gives an overview on the problems typically coming along with fermentation process optimization and scale up, and presents currently applied scale up strategies while considering future technologies, with emphasis on escherichia coli as one of the most commonly fermented organisms. Chapter 18 scale up of polygalacturonase production by solid state fermentation process siumara r. Scale up projects often require implementation of new equipment or modification of existing equipment. Davis, master of science utah state university, 2009 major professor. This presentation will describe the challenges faced during fermentation scale up process for production of new chemical entities with reference to some case studies. This presentation will describe the challenges faced during fermentation scaleup process for production of new chemical entities with reference to some case studies. Scaling up industrial microbial processes for commercial production is a. Strainprocess b used for successful commercial scaleup predictable scaleup robust commercial performance,000l demonstration commercial 50x scaleup average fermentation performance 50 commercial scale runs vs. Optimizing scaleup fermentation processes sciencedirect.
Comparing the scaleup of anaerobic and aerobic processes. Scaleup of escherichia coli fermentation from small scale to pilot scale using eppendorf fermentation systems bin li and ma sha eppendorf inc. Production processes for monoclonal antibodies intechopen. In reality many fermentation technologists are not aware that during most times of their work they are doing scale down studies maybe the phrase scale up has more impact factor than scale down studies. Scaleup definition act of using results obtained from laboratory studies for designing a prototype and a pilot plant process.
High content of waterinsoluble solids wis is required for simultaneous saccharification and cofermentation sscf operations to reach the high ethanol concentrations that meet the technoeconomic requirements of industrialscale production. The scaleup of microbial batch and fedbatch fermentation processes. Challenges in fermentation scale up process for production of. The relative sizes of the scaling groups for this plant are shown in table r7. In order to make the scale up process cost effective, the strains need to be improved to achieve several fold improvement in titers. Growth of anaerobic processes historically scale up of aerobic processes fuel to food processes ici, ltd. In addition to an overview of the theory of multiscale analysis for fermentation process, examples of scaleup practice combining microbial. Increase in scale means an increase in volume and the problems of process scaleup are due to the different ways in which process parameters are affected by the size of the. With explicit guarantee of the good quality of upstream technology, creative enzymes offers fermentation and scaling up service for enzyme industrial production. Due to the larger size and scale of industrial fermentation setups it is vital to succeed beforehand studies of possible complications, due to increase in scale, and to sort out ways to tackle them. Proof of concept and feasibility study for large scale production l. According to the derivation of the term, it signifies merely a gentle bubbling or boiling condition.
Key factors for bioprocess technology selection, scaleup and engineering of new facilities biocatalyst raw materials process technologies products scale economics s cale e conomics b. The production of rhamnolipid was greatly enhanced by fermentation optimization with palm oil as substrate. An initial medium 250l containing 240gl dry powder of jerusalem arti. Scale up of escherichia coli fermentation from small scale to pilot scale using eppendorf fermentation systems bin li and ma sha eppendorf inc. As the size of the fermentation increases during scale up, various parameters do not show predictable linear co relationship that is the major problem there is no. The art of fermentation has been around for centuries. Scale up of polygalacturonase production by solid state.
Variables to be considered when changing fermentation scale implementing a scaling activity summary references and. However, as fermentation facilities usually are not strictly designed according to scaleup criteria and the process conditions in the culture vessels thus may differ significantly and since any strategy and model can only insufficiently consider and reflect the highly complex interdependence and mutual interaction of fermentation parameters. Rhamnolipid production, characterization and fermentation. Hence, scale up studies not only help understanding the technical components of a large scale fermentation setup but also reduce the economic risk involved in the case of direct investment on large scale production. Scaleup would be very simple if all parameters affecting bacteria remained the same. Specific scaleup issues in fermentation contaminants, sterilization, and septic control contaminants virtually unavoidable with scaleup control of contamination depends either on eradicating all contaminants entirely or accepting some manageable level of contamination. Best practices for successful scale up of industrial fermentation processes. Then, when the scale is increased, the broth will become more and more heterogeneous.
Process development, engineering and economics by edi d. This process is the important step for transferring benchtop fermentations to mass production. The method employed to increase the scale of a culture depends on whether the cell is proliferating in suspension or is anchored to the substrate. Process optimization is generally performed in benchscale bioreactors, and then scaled up to larger scale for commercial production 20. Jul 03, 2017 scale up studies scale up studies are studies carried out at the laboratory or even pilot plant scale fermenters to yield data that could be used to extrapolate and build the large scale industrial fermenters. Effect of fermentation on the growth of escherichia coli strain.
Shortcomings of available methods and potential routes to better ones are discussed in this article. The best way to prepare the scaling up of a process is to first scale down to the pilot scale of the conditions of culture that will be used at the final scale of production. The purpose of a seed train is to propagate cells to a desired mass for inoculation into the production bioreactor. The fermentation process basically consists of inoculum preservation, inoculum buildup, prefermenter culture and finally production fermentation. To do so, we first investigated engineering parameters critical for scaling up fermentation processes, such as vessel and impeller geometry, oxygen transfer rate. The fundamental challenges of such processes are related to the high viscosity and inhibitor contents of the medium. Recognition of and attention to scaledependent fermentation parameters is fundamental to reducingeven eliminatingfermentation as a scaleup risk. Reference number2 process scaleup is the means by which innovations in the chemical industry are put into place in industrial facilities the vast majority of innovations in the chemical process industries are developed at laboratory scale at sizes better. Mixing time t mix, defined as the period of time required for the homogeneous distribution of a small volume of pulsating material in the bulk of the liquid, was used for scale up to adjust proper mixing conditions in large vessels. In large fermentors, oxygen can be depleted in some area of the reactor. Of operations cell and cell products fermentation facility waksman. Scaleup of escherichia coli fermentation from small scale. To increase product yields and to ensure consistent product quality, key issues of industrial fermentations, process optimization and scale up. Scaleup means increasing the scale of a fermentation, for example from the laboratory scale to the pilot plant scale or from the pilot plant scale to the production scale.
However, limitation of using t mix as scale up criteria is that it increases markedly with the. Optimization is expected to increase the yield of the final product but the process must be compliant with good manufacturing practices,the. A read is counted each time someone views a publication summary such as the title, abstract, and list of authors, clicks on a figure, or views or downloads the fulltext. Challenges in fermentation scale up process for production. Scale up would be very simple if all parameters affecting bacteria remained the same. Keeping the working volume constant furthermore simplifies culture scaleup based on constantpowertovolume strategy 1.
In a major feat of chemical engineering, the company rebuilt an old ice plant, which had the refrigeration machinery required for submerged fermentation, and opened the worlds first largescale penicillin facility on march 1, 1944. A beginners guide to bioprocess modes batch, fed batch. In scaling up a conventional stirred tank fermentor stf the designer must provide for at least, and at the lowest possible cost. Fermentation is the splitting up of a body into several parts, by a power within itself, or imparted to it by another body in contact with it. Jun 19, 2015 different rhamnolipids had different performances in interfacial tension. Request pdf optimzing scaleup fermentation processes there are many aims associated with the optimization of fermentation processes.
Methods for scaling up of cell cultures orbit biotech. Jan 03, 2008 in reality many fermentation technologists are not aware that during most times of their work they are doing scale down studies maybe the phrase scale up has more impact factor than scale down studies. Largescale production has revolutionized the market for monoclonal antibodies by boosting its production and becoming a more practical method of production. Optimizing scaleup fermentation processes michel thiry and doriano cingolani there are many aims associated with the optimization of fermentation processes. This article gives an overview on the problems typically coming along with fermentation process optimization and scale up, and presents currently applied scaleup strategies while considering future technologies, with emphasis on escherichia coli as. Scale up and scale down of fermentation processes practical. Scaleup test in 500l fermentor with agitation after a scaleup test in a 50l agitating fermentor, fermentation was investigated using a 500l agitating fermentor i. Hence, scale up studies not only help understanding the technical components of a largescale fermentation setup but also reduce the economic risk involved in the case of direct investment on large scale production. Scaleup of escherichia coli fermentation from small.