Successive scaling

Process development with particular attention to process profitability and safety and minimization of the environmental impact is presented in Chapter 5. A brief description of the present practice in scale-up, development, and production planning is given and the most promising trends and achievements are presented. Recommendations are given how to achieve success in the scale-up of a process a successful scale-up can be defined as the procedure that allows the same yields and product distribution in a full-scale plant as on a small scale. 

Hydrophobic interaction chromatograph (HIC), while very attractive in principle, has proved difficult to scale up for processing. A recent series of articles explores some of the unique problems associated with process-scale HIC. Load sample preparation20 must be carefully examined to prevent protein aggregate formation in the presence of the relatively high salt concentrations used in this technique. Successful scale-up also requires the setting of wide specifications to accomodate routine variations in the feed.21 The effect of the salt concentration on capacity may be somewhat more... 

The first generation process was rapidly and successfully scaled up to provide multi-ton quantities of bulk drug to adequately supply needs through phase III, drug filing and launch. 

Avidan and Edwards (1986) successfully scaled up from bench scale to demonstration plant from 0.04 m to 0.6 m diameter while maintaining nearly 100% conversion for a fluid bed methanol to gasoline process. In this case, they ran at a superficial gas velocity which was high enough to be in the turbulent flow regime suppressing bubbles. By this technique they eliminated the losses associated with gas bypassing in bubbles. 

Understanding the effect of reactor diameter on the volumetric mass transfer coefficient is critical to successful scale up. In studies of a three-phase fluidized bed bioreactor using soft polyurethane particles, Karamanev et al. (1992) found that for a classical fluidized bed bioreactor, kxa could either increase or decrease with a change in reactor diameter, depending on solids holdup, but for a draft tube fluidized bed bioreactor, kxa always increased with increased reactor diameter. 

Avecia and others have successfully scaled-up the IPA process to prepare a number of products in high optical purity in a simple and efficient reaction [lc, 48]. 

Table 3.5 shows that the study of chemical kinetics is critical in successful scale-up of catalytic systems, of gas-phase controlled systems, and of continuous tank stirred reactors (CSTR). For scale-up of batch systems consisting of gas or liquid compounds, chemical kinetics and heat transfer effects must be studied because the combination of these phenomenon determine the conditions for a runaway and thus involve the safety of the operation. 

For a gas-liquid reaction which is gas-phase controlling, the chemical kinetics must be well understood. The importance of laboratory studies must therefore be emphasized. However, for successful scale-up, pilot plant studies are very critical because of the difficulties in reliably modeling gas behavior on a small scale (due to hydrodynamics) and its influence on reaction rates. 

Suffice it to say that almost all operations on scale are possible if money and time are not issues of course, money rarely flows freely, and time is one of the major issues for developing drugs. Operations are almost always changed in progressing from the discovery route to scale-up. The best approach for rapid, successful scale-up is to scale down operations to the lab, and then develop processes that can be scaled up by mimicking conditions that will subsequently be encountered on scale. 

CONSIDERATIONS FOR SUCCESSFUL SCALE-UP TO TOX BATCHES AND PHASE 1 MATERIAL... 

Scheme 2.7. Successful scale-up through continuous processing.

This preparative procedure may be successfully scaled up by at least a factor of 3, with due caution being taken to monitor the pressure in the reaction vessel. 

The procedure used in this section, which could be called successive scaling, does indeed provide additional information. A simpler example of successive scaling will be presented in the next section. 

The initial emulsification studies employed a 1 L reactor vessel with baffles originally designed for fermentation processes. Subsequent studies were successively scaled up from 1 L to 3, 10, and 100 L. Variations due to differences in reactor configuration were minimized by utilizing geometrically similar reactors with approximately the same D/Tratio (i.e., 0.36-0.40). Maa and Hsu contended that separate experiments on the effect of the baffle area... 

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. 

Although many types of pellet dosage forms have been introduced in the marketplace, a greater understanding is needed of the role of excipients, equipment, process variables, and controls involved in the pelletization process and those that govern successful scale-up from laboratory to... 

Successful scale-up of the tableting process also requires control of the raw materials used in compaction. Typically, pharmaceutical excipients vary in their physicochemical properties, which result in batch-to-batch variations. The tableting process, especially direct compression processes where there is limited raw material alteration before compaction, is susceptible to raw material variation, which may be magnified upon scale-up. Compaction science affords the ability to fingerprint raw materials, including the drug substance, to determine if the same compaction properties will be observed from batch to batch. This also allows for a rational approach for determining alternate vendor sources of the same materials. 

By showing robustness around these parameters, there is increased confidence that the formulation and process can be successfully scaled-up under target conditions for these parameters. 

By identifying critical process parameters early on in the development process, a robust formulation was developed and successfully scaled-up... 

Effective product and process optimization play a prominent role in any successful scale-up study. As an illustration, this case study summarizes the initial development, and subsequent scale-up, of a Wurster process designed to facilitate the application of an aqueous ethylcellulose dispersion to drug-loaded pellets. At the same time, it was intended to deal, up front, with some of the idiosyncrasies of such a coating system that often influence the functionality of the final dosage form. 

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. 

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