The Scaling-up Process

Tkble 8-2 shows columns whose diameters have increased from 4.6 to 150 mm, a factor of over thirty times. The loading capacity has increased from a few milligrams per run to several grams per run on the process scale column. The actual loading that can be achieved on a particular size of column will be highly dependant upon the extent of separation of the peak of interest from the peaks of undesired components. If this separation is large the column may be loaded at considerably higher levels than those indicated in Table 8-2. 

There are examples in the literature where columns are loaded to the extent of greater than 10 mg loading to 1 g of packing. In supercritical fluid chromatography the limit of loadability is more likely to be a limit imposed by the solubility of the sample in the supercritical fluid rather than the capacity of the column for the quantity of substance applied. 

8 Scaling-up of Supercritical Fluid Chromatography to Large-Scale Applications 

Column Diameter (mm) Nominal imperial equivalent (inches) Column volume (mL) Packing required (dry weight, g) 

Column volume calculated by assuming a standard length of 250 mm. A packing density of 0.7 g mL has been assumed for the calculation of the weight of dry packing required to fill these columns. Naturally, this density will vary from packing type to type and must be calculated individually for the particular column desired. 

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Test runs using a 150 mm diameter fluid bed coater indicated that a batch of 2 kg of material could be coated using a liquid spray rate of 10 ml/min for 50 minutes and a fluidizing gas rate of 40 scfm. It is desired to scale-up this process to a batch size of 200 kg of bed material. For the scaled up process, determine the bed size the liquid and airflow rates and the new run time. 

One primary goal is to conserve selectivity throughout scale-up. This means attempting to use the same separation chemistry in development that will eventually be used in production. This avoids the need to re-optimize in each stage of the scale-up process. It is desirable to use the same support matrix to avoid unforeseen matrix effects causing uimecessary modification of developed procedures. 

Yabannavar et al. [81] proposed a proportionality relationship valid for spin-filters based on an analogy to Eq. (15). They defined the Reynolds number based on the tangential velocity at the screen surface. Since in spin-filters the permeation velocity, or perfusion flux, is given by Eq. (16), and it can be assumed that the screen porosity e will be maintained constant throughout the scale-up process, it is possible to write a proportionaHty relationship for the ratio from drag to lift force in spin-filters as given by Eq. (17). 

Dale WJ. The scale-up process optimize the use of your pilot plant. Abstract 108c, Session 108 on Experimental Strategies for Pilot Plants, 1996 Spring Meeting, Am. Inst. Chem. Engrs., New York. 

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. 

Still, we can offer some simple guidelines that can help the practitioner wade through the scale-up process ... 

To fluidize and thus granulate and dry the product, a certain quantity of process air is required. The volume of the air required will vary, based upon the amount of material that needs to be processed. The ratio of drying capacity of the process air and quantity of the product needs to be maintained constant throughout the scaling-up process. However, some suppliers of the equipment provide higher drying capacity for their laboratory unit... 

In many companies, the scale-up process may include or overlap with the validation process. In any case, demonstration of the process in the production environment at full scale, using the materials, equipment, procedures, and personnel established in production, is required. Often, multidisciplinary teams are arranged to manage the scale-up, and the overall roles and responsibilities for those involved with the product may change. Typically, extensive documentation, including protocols and reports, is involved, as... 

Unlike the processes described elsewhere in this book, the film-coating process is inherently much more complex, since the list of parameters that contribute to overall success is, potentially, exhaustive. Thus, the complexities of the scale-up process are potentially more challenging. In basic terms, these three components of the film-coating process all contribute, in a very much interactive manner, to the overall success of the process ... 

An important fact to be recognized, however, is that an extensive database relating to the coating process in question has been established, and key process variables (including their interactive effects) have been identified, providing a sound platform from which to begin the scale-up process. 

These idiosyncrasies, in terms of airflow requirements, do complicate matters, however, when scaling-up from one type of coating pan to another. These complications arise when applying the simple predictions (based on Equation 1) for spray rates. If the scale-up process involves switching from a laboratory-scale fully perforated pan to a production-scale Hi-Coater, there is a risk that the predicted spray rates will be understated. For the sake of the calculation, a useful rule of thumb is to double the value for the actual air volume that will be employed in the larger-scale Hi-Coater, and to use that value solely for the purposes of the calculation. 

In summary, the results shown in Figures 7-10, which only represent data for two distinct types of spray guns, provide clear warning of the potential problems that can occur if, during the scale-up process, commonly seen... 

In contrast to pan-coating processes, some characteristics of fluid-bed processes that may feature strongly in the scale-up process include the fact that ... 

This volume is designed to provide some answers that can facilitate the scale-up process. The main underlying theme that can be detected in almost every chapter of the book is reference to dimensional analysis, a... 

A systematic, generalized approach for the scale-up of granular mixing devices is still far from attainable. Clearly, more research is required both to test current hypotheses and to generate new approaches to the problem. Still, we can offer some simple guidelines that can help the practitioner wade through the scale-up process. 

There are several uses of tablet press instrumentation in the scale-up process itself. One of these involves obtaining a sample of the scale-up batch and compacting that sample on the pilot-plant or research instrumented tablet press on which the formulation has been previously evaluated. Similarity of the fingerprint or the various research plots (Heckel, force-displacement, radial vs. axial plots) is evidence that the scale-up batch is similar to the previously evaluated research batch [2]. 

The alternative would be to obtain a portion of the formulation, lake it back to the instrumented press used in the pilot plant or in R D, and perform the same evaluation as was performed on the smaller batches. By this technique, one can evaluate the scale-up process for all the other operations and then note any differences in performance on the production press. 

Although there are many tablet properties to be evaluated, the most important to observe during the scale-up process are tablet hardness (or tensile strength) and tablet dissolution. The former could be affected significantly by press speed (if the... 

The availability of such a variety of equipment often adds an extra degree of complexity to the scale-up process. Geographical preferences in equipment... 

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