Scale-up considerations

Dry milling techniques are more difficult to scale across sets. While the output PSD is largely a function of mill energy input (tip speed for pin mill and gas pressures 

We gratefully acknowledge Pavan Akkisetty of Purdue University for his help in building a database of milling references. 

Amidon GL, Lennemas H, Shah VP, Crison JR. 1995. A theoretical basis for a biophar-maceutic drug classification the correlation of in vitro drug product dissolution and in vivo bioavailability. Pharm. Res. 12 413-420. 

Curl R, Amidon G. 1993. Estimating the fraction dose absorbed from suspensions of poorly soluble compounds in humans A mathematical model. Pharm. Res. 10 264-270. 

Waiver of in vivo bioavailability and bioequivalence studies for immediate-release solid oral dosage forms based on a biopharmaceutics classification system. U.S. Department of Health and Human Services Food and Drug Administration Center for Drug Evaluation and Research (CDER), August 2000. 

The overall strategy for the scale-up of this study was to select the diameter and the length of the reactor, size and shape of catalyst particles, and the superficial velocity of liquid in such a way that the effects of nonideal flow together with mass and heat 

Pressure drop is usually negligible in a short laboratory-scale reactor with low superficial velocities. In the scale-up, the reactor becomes much longer than in the laboratory scale and 

Catalyst deactivation was present in the laboratory-scale experiments even for the better catalyst, although the 

As the superficial velocity of liquid was adjusted upward to provide exactly the same mean residence time for the pilot case as was used for the laboratory-scale experiments, the liquid pressure drop became 1 kPa in the 5 m reactor. This was only 0.1 % of total pressure for the lower pressure case and was negligible. 

Experimental data of stearic acid decarboxylation in a laboratory-scale fixed bed reactor for formation of heptadecane were evaluated studied with the aid of mathematical modeling. Reaction kinetics, catalyst deactivation, and axial dispersion were the central elements of the model. The effect of internal mass transfer resistance in catalyst pores was found negligible due to the slow reaction rates. The model was used for an extensive sensitivity study and parameter estimation. With optimized parameters, the model was able to describe the experimentally observed trends adequately. A reactor scale-up study was made by selecting the reactor geometry (diameter and length of the reactor, size and the shape of the catalyst particles) and operating conditions (superficial liquid velocity, temperature, and pressure) in such a way that nonideal flow and mass and heat transfer phenomena in pilot scale were avoided. 

If you have several years experience in scale-up, you will see a lot and will learn from what goes right and from mistakes. Chances are that many of you do not have decades of scale-up experience. If you are faced with scaling from the laboratory, my best advice is to seek counsel from those that are experienced. 

Coincidentally, another member of our group, also a freshly minted Ph.D. chemist, had the same task for a different process. We took different approaches. 1 took a botde of laboratory-prepared slurry and brought it to the plant. I talked to the operators who ran the centrifuge and solicited their advice. I also consulted with some of the experienced people in our group. Based upon the advice given, I selected a cloth and trialed it on a laboratory centrifuge. It worked well and when done in the plant, the separation went smoothly. 

The other chemist took a different approach. He did statistical laboratory experiments with dozens of cloth materials. After weeks of research and some very impressive weekly reports, he identified an optimum cloth. When the process went to the plant, the separation was a disaster. The material would not separate in the centrifuge. After several delays and switching cloths, the separation was finally done. The delays put the plant behind schedule and did not do much for the credibility of our group. All of this could probably have been avoided by consulting experienced people prior to the scale-up. 

On the topic of communication regarding sctde-ups, let me relate another true story. A scale-up I did early in my career involved the bromination of a ketone. It was done in a pilot plant on a scale of 100 gallons. The reaction proceeds through the enol so is acid catalyzed. 

A solution of the ketone in water is made. A small amount of HBr is added and then bromine gradually added. The reaction is rapid and exothermic but can be controlled by the rate of bromine addition. For each equivalent of bromine added, an equivalent of HBr is formed. Initially the HBr dissolves in the water but eventually the water becomes saturated and the HBr evolves as a gas from the reaction. In the lab, it is easy to contain the HBr. I passed the gas through a flask containing a sodium hydroxide solution. In the pilot plant, I planned to pass the gas counter-current through a water stream. The water absorbs the HBr gas. Based upon HBr solubility in water and bromine 

Generally batch crystallizations can be quite robust if designed the right way, however scale-up is not an easy task and several points have to be taken into consideration. 

Physical models of commercial fluidized bed equipment provide an important source of design information for process development. A physical model of a commercial fluidized bed processor provides a small-scale simulation of the fluid dynamics of a commercial process. While commercial processes will typically operate at conditions making direct observation of bed fluid dynamics difficult (high temperature, high pressure, corrosive 

Cold flow studies have several advantages. Operation at ambient temperature allows construction of the experimental units with transparent plastic material that provides full visibility of the unit during operation. In addition, the experimental unit is much easier to instrument because of operating conditions less severe than those of a hot model. The cold model can also be constructed at a lower cost in a shorter time and requires less manpower to operate. Larger experimental units, closer to commercial size, can thus be constructed at a reasonable cost and within an affordable time frame. If the simulation criteria are known, the results of cold flow model studies can then be combined with the kinetic models and the intrinsic rate equations generated from the bench-scale hot models to construct a realistic mathematical model for scale-up. 

Yang et al. (1995) described the application of this scale-up approach. Comprehensive testing programs were performed on two relatively large-scale simulation units for a period of several years a 30-cm diameter (semicircular) Plexiglas cold model and a 3-m diameter (semicircular) Plexiglas cold model, both operated at atmospheric pressure. 

The primary applications for large-scale jetting fluidized beds are in the area of coal gasification as described by Yang et al. (1995), Kojima et al., (1995), and Tsuji and Uemaki (1994). Smaller scale applications are for fluidized bed coating and granulation to be discussed in Chapter 6. 

Comparisons between analytical and synthetic systems are not always easy to draw in view of the different conditions employed. Thus, the thermodynamically reversible and mechanistically simplistic hydrogen and chlorine evolution reactions, well behaved in analytical studies at platinized platinum, are both beset (chlorine most severely) in large-scale chlor-alkali cells by adherence of gas bubbles to the electrode surface. 

This can be ameliorated by ultrasound.35 Furthermore, the irreversible oxygen-evolution reaction which competes with chlorine evolution, causing a problem in the commercial application, is differently affected by insonation, offering a possible practical benefit. 

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Some mycehal fermentations exhibit early sporulation, breakup of mycehum, and low yields if the shear is excessive. A tip speed or 250 to 500 cm/s (8 to 16 ft/s) is considered permissible. Mixing time has been proposed as a scale-up consideration, but httle can be done to improve it in a large fermenter because gigantic motors would be required to get rapid mixing. Culturing cells from plants or animals is beset by mixing problems because these cell are easily damaged by shear. 

Establishing the process sensitivity with respect to the above-mentioned factors is crucial for further scale-up considerations. If the sensitivity is low, a direct volume scale-up is allowed and the use of standard batch reactor configurations is permitted. However, many reactions are characterized by a large thermal effect and many molecules are very sensitive to process conditions on molecular scale (pH, temperature, concentrations, etc.). Such processes are much more difficult to scale up. Mixing can then become a very important factor influencing reactor performance for reactions where mixing times and reaction times are comparable, micromixing also becomes important. 

The different areas outlined above for scale-up considerations all provide approaches to reducing cycle time and maximizing throughput ... 

Mehta, A. M., Scale-Up Considerations in the Fluid-Bed Process for Controlled Release Products, Pharm. Tech., 12 46-52(1988)... 

Scale-up Considerations for Different Forms of Plant Tissue Culture... 

The first fixed-bed methanol-to-gasoline (MTG) plant design and scale-up considerations. Stud. Surf. Sci. Catal., vol. 36, Elsevier, Amsterdam,... 

Scale-up considerations for batch flocculation in stirred tanks indicate that similar results are obtained with ... 

It is important to add heat transfer scale-up considerations to the scale-up approach for liquid parenteral solutions as heat transfer applications may play a considerable role in preparation of these products. For heat transfer applications, constant horsepower per unit volume is used to achieve approximately similar heat transfer coefficients for the same type of impeller. This approach is a close approximation since the effect of horsepower on the heat transfer coefficient (ho) is relatively small ... 

For purification, scale-up considerations are important even in the earliest phases of development. It is important to avoid the use of purification techniques of limited scale-up potential even for early clinical production because thorough justification of process changes and demonstration of biochemical comparability are necessary prior to product licensure. For successful scale-up, it is important to understand the critical parameters affecting the performance of each purification step at each scale. Conversely, it is important to verify that the scaled-down process is an accurate representation of the scaled-up process, so that process validation studies, such as viral clearance and column lifetime studies, can be performed at the laboratory scale. 

Hua J, Erickson LE, Yiin T-Y, Glasgow LA. A review of the effects of shear and interfacial phenomena on cell viability. Grit Rev Biotechnol 1993 13(4) 305-328. Tramper J, de Gooijer KD, Vlak JM. Scale-up considerations and bioreactor development for animal cell cultivation. Bioprocess Technol 1993 17 139-177. Griffiths B, Looby D. Scale-up of suspension and anchorage-dependent animal cells. Methods Mol Biol 1997 75 59-75. 

Scale-Up Considerations Drying-Process Air Dew Point and Dry Bulb Temperature... 

Scale-Up Considerations Spraying-Spray Rate and Droplet... 

Scale-Up Considerations Product Moisture Content During... 

J. Tramper, K. D. de Gooijer. J. M. Vlak. Scale-up considerations and bioreactor development for animal cell cultivation. Bioprocess Technol 17 139-177, 1993. 

This chapter deals with the design of a pilot plant facility. Although this chapter discusses many aspects of pilot plant scale-up considerations, it is not meant as a treatise on process scale-up. Many other authors in this book discuss this subject more thoroughly. All discussions on process scale-up in this chapter are presented to serve as examples of the thought process that must be considered when engaged in the design of a facility. 

Convection mixers use a different principle for blending. These mixers have an impeller. This class includes ribbon blenders, orbiting screw blenders, vertical and horizontal high-intensity mixers, as well as diffusion blenders with an intensifier bar. Scale-up considerations are similar to those for the tumble blenders. 

On the basis of scale-up considerations from 0.4-L runs, each sample extraction was conducted at 1950 50 lb/in.2 and 37-45 °C, lasted about 110 min, and involved passing approximately 11,200 standard liters of carbon dioxide through the aqueous solution. Because pressure-flow rate excursions might occur in the large-scale apparatus and lead to the rupture of glass traps, a series of three stainless steel impingers maintained at —76 °C were used to collect the organics present in the effluent carbon dioxide stream. 

Mehdizadeh, M., Engineering and scale-up considerations for microwave induced reactions, Res. Chem. Intermed., 1994, 20, 79. 

Using characteristic values is a widespread and helpful means. An example for material characteristics is the specific energy input based measured in kWh/kg (see Section 6.5.1), while the available torque/axis distance measured in Nm/m3 is a machine characteristic. Dimensionless parameters (with the unit 1) play an important role for scale down/scale up considerations. The Reynolds number is a known dimensionless parameter, determining whether flow is laminar or turbulent. However, it is of little importance for extruder scale downs/scale ups. 

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