Scale-up problems

Using a draft tube in the tank for solids suspension introduces another, different set of variables. There are other relationships that are veiy much affected by scale-up in this type of process, as shown in Fig. 18-22. Different scale-up problems exist whether the impeller is pumping up or down within the draft tube. 

Isolation procedures for many biochemicals are based on chromatography. Practically any substance can be selected from a crude mixture and eluted at relatively high purity from a chromatographic column with the right combination of adsorbent, conditions, and eluant. For bench scale or for a small pilot plant, such chromatography has rendered alternate procedures such as electrophoresis nearly obsolete. Unfortunately, as size increases, dispersion in the column ruins resolution. To produce small amounts or up to tens of kilograms per year, chromatography is an excellent choice. When the scale-up problem is solved, these procedures should displace some of the conventional steps in the chemical process industries. 

For some scale-up problems, generalized coiTclations as shown in Figures 7-11, 7-12, 7-13, and 7-14 are available for scale-up. However, there is much diversity in the process to be scaled-up, and as such no single method can successfully handle all types of scale-up problems. 

Similarity concepts use physical and mathematical relations between variables to compare the expected performance of mixing/agitation in different sized systems [33]. This is usually only a part answer to the scale-up problem. 

Electrochemical processes are particularly well suited for the manufacture of fine chemicals in view of their high sjjecificity (almost comparable to that offered by enzymes), the smaller number of steps required, adoption of milder conditions, lack of scale-up problems, avoidance of effluents, etc. The ease with which oxidation and/or reduction can be carried out with the practically mass-free clean electrons makes electrochemical processes well suited for such jobs, including paired synthesis in effect, we use electricity as a reagent . Consider a standard chemical oxidant like manganic or chromic sulphate. Here, a stoichiometric amount of the reduced salt will be formed the disposal of which can be a serious problem. If we adopt an electrochemical process, then the reduced salt is converted into the desired oxidized salt. 

Due to the complexity of the problem, it is generally accepted that we will not reach the optimal reactor design and ojjerating variables, but still we would like to design and operate the reactor safely and near the optimum. Further in this section, we will give a general discussion of. scale-up methods for chemical processes, in particular with respect to chemical reactors suitable for the manufacture of fine chemicals. Next, we will discuss how to obtain reasonable quantitative relationships necessary for optimal and safe scale-up according to the art. The reader can find an extensive treatment of scale-up problems in the book of Bisio and Kabel(1985). 

Figure 2. Very large equipment built to study scale-up problems. (From May, 1959.)...

Despite the scaling-up problems, the following industrial processes have been proposed, and disclosed mainly in the patent literature ... 

The first example involves flammability issues that are not specifically covered in this Guidelines book. However, the discussion here is highly important for safe process design considerations and represents a good example of the problems of scale-up from test data. Runaway reactions may indeed result in the production of flammable gases so an understanding of the scale-up problems is critical. 

Prior to formulating a drug substance into a dosage form, the desired product type must be detemined for planning the product formulation activities. Then, various initial formulations are developed and then evaluated for selected parameters, such as drug-release profile, bioavailability, clinical effectiveness, and for any scale-up problems. The best formulation is selected and becomes the master formula. Each batch of the product subsequently prepared must meet the specifications established in this master formula. 

Finally, the use of PAT should not be limited to existing processes and products but is especially attractive in the R D and scale-up of new processes and products. PAT is especially effective in scale-up. As PAT involves consideration of all monitored variables and not only an empirical selection of some of those variables, and since in-process monitoring techniques are normally multiparametric (e.g., near-infrared spectra of a whole sample), they will be more suited to capture scale effects present in the sample s matrix that show up clearly in a consolidated multivariate analysis of quality and operating variables, thus helping the skillful engineer or scientist to pinpoint and solve scale-up problems thus resulting in a much faster process prototyping and scale-up. 

It was found that heating a dilute solution of imidoyl chloride 130 in n-xylene afforded the chloroimidazopyridine 131 in 73% yield. The yield of 131 could be improved slightly to 81% if the electrocyclization was run in a microwave reactor, but because of scale-up problems this procedure was not normally used. In the case of imidoyl bromide 132, the electrocyclization afforded only a modest 46% yield of bromopyridine 133, along with about 13% of recovered starting material. With the benzyloxymethyl (BOM)-protected imidoyl chloride 134, chloropyridine 135 was obtained in 84% isolated yield upon heating in n-xylene (Equation 46) <20060L1443>. 

A clue to the resolution of the scale-up problem for liquids and semisolids resides in the recognition that their processing invariably involves the... 

Modular scale-up involves the scale-up of individual components or unit operations of a manufacturing process. The interactions among these individual operations comprise the potential scale-up problem, i.e., the inability to achieve sameness when the process is conducted on a different scale. When the physical or physicochemical properties of system components are known, the scalability of some unit operations may be predictable. 

Unfortunately, the publication by Williams and coworkers is one of the only reports of a scale-up problem involving liquids or semisolids in the pharmaceutical literature. A number of papers that purport to deal with scale-up issues and even go so far as to compare the properties of small versus large batches failed to apply techniques, such as dimensional analysis, that could have provided the basis for a far more substantial assessment or analysis of the scale-up problem for their system. Worse yet, there is no indication of how scale-up was achieved or what scale-up algorithm(s), if any, were used. Consequently, their usefulness, from a pedagogical point of view, is minimal. In the end, effective scale-up requires the complete characterization of the materials and processes involved and a critical evaluation of all laboratory and production data that may have some bearing on the scalability of the process. 

A QUASI-CONTINUOUS GRANULATION AND DRYING PROCESS (QCGDP) TO AVOID SCALE-UP PROBLEMS... 

Dorr B, Leuenberger H. Development of a quasi-continuous production line—a concept to avoid scale-up problems. In Leuenberger H, ed. Preprints First European Symposium on Process Technologies in Pharmaceutical and Nutritional Sciences, PARTEC 98 Niimberg, 1998 247-256. 

Some of the researchers have addressed scale-up problems by adopting the semi-continuous granulation techniques (135,136). 

The most common scale-up problems are related to bulk density, powder flow, compactibility, and lubricant distribution. Therefore, any discussion of the issues of scaling-up capsule Ailing must take into account the design and operating principles of Ailing machines and their formulation requirements. 

Imagine that you have successfully scaled up a mixing or a granulating process from a 10-liter batch to a 75-liter and then to a 300-liter batch. What exactly happened You may say, I got lucky. Apart from luck, there had to be some physical similarity in the processing of the batches. Once you understand what makes these processes similar, you can eliminate many scale-up problems. 

One way to eliminate potential scale-up problems is to develop formulations that are very robust with respect to processing conditions. A comprehensive database of excipients detailing their material properties may be indispensable for this purpose. However, in practical terms, this cannot be achieved without some means of testing in production environment and, since the initial drug substance is usually available in small quantities, some form of simulation is required on a small scale. 

As tablet formulations are moved from small-scale research presses to high-speed machines, potential scale-up problems can be eliminated by simulation of production conditions in the formulation development lab. In any process transfer from one tablet press to another, one may aim to... 

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