Scale-of-Agitation Approach

The basis of the scale-of-agitation approach is a geometric scale-up with the power law exponent, = 1 (Table 1). This provides for equal fluid velocities in both large- and small-scale equipment. Furthermore, several dimensionless groups are used to relate the fluid properties to the physical properties of the equipment being considered. In particular, bulk-fluid velocity comparisons are made around the largest blade in the system. This method is best suited for turbulent flow agitation in which tanks are assumed to be vertical cylinders. 

The analysis proceeds as follows. First, determine the D/T ratio of the tank, based on the largest impeller, in which the original (usually research and development) batches had been compounded. It is also necessary to know the rotational speed and the horsepower of the mixer used. 

Q Effective pumping capacity or volumetric pumping flow in cm /sec 

The only two product physical properties needed are density and viscosity. Generally, parenterals, as the most solution-type products, will follow Newtonian fluid behavior and may also be considered incompressible. Therefore, point densities and viscosities can be used satisfactorily. 

The next step in the analysis is to calculate the impeller Reynolds number achieved during this original compounding using Equation (12). The impeller Reynolds number must be 2000 to proceed with analysis (3). 

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To illustrate the actual application of the scale-of-agitation approach to scale-up, the above method was applied to the scale-up of typical injectables solution from 378-L pilot batch to a 3780-L production-size batch. The example product is a Newtonian fluid with density of 1.018 g/cm and a viscosity of 0.0588 g/cm/sec (5.88 cps). The tank used in the manufacturing of the pilot batch had the following parameters ... 

The basic principles employed in the preparation of parenteral products do not vary from those widely used in other sterile and non-sterile liquid preparations. However, it is imperative that all calculations are made in an accurate and most precise manner. Therefore, an issue of a parenteral solution scale-up essentially becomes a liquid scale-up task, which requires a high degree of accuracy. A practical yet scientifically sound means of performing this scale-up analysis of liquid parenteral systems is presented below. The approach is based on the scale of agitation method. For singlephase liquid systems, the primary scale-up criterion is equal liquid motion when comparing pilot-size batches to a larger production-size batches. 

On a qualitative basis the Reynolds number can be appreciated by considering the speed of the impeller tips. At a constant stirring rate, the turbulence of a mixture increases greatly as the radius of the impeller increases. A quantitative approach to scaling down agitation has been described [9]. 

In the simplest case, the feed solution consists of a solvent A containing a consolute component C, which is brought into contact with a second solvent B. Eor efficient contact there must be a large interfacial area across which component C can transfer until equiHbrium is reached or closely approached. On the laboratory scale this can be achieved in a few minutes simply by hand agitation of the two Hquid phases in a stoppered flask or separatory fuimel. Under continuous flow conditions it is usually necessary to use mechanical agitation to promote coalescence of the phases. After sufficient time and agitation, the system approaches equiHbrium which can be expressed in terms of the extraction factor S for component C ... 

This paper describes work on equipment and instrumentation aimed at a computer-assisted lab-scale resin prep, facility. The approach has been to focus on hardware modules which could be developed and used incrementally on route to system integration. Thus, a primary split of process parameters was made into heat transfer and temperature control, and mass transfer and agitation. In the first of these the paper reports work on a range of temperature measurement, indicators and control units. On the mass transfer side most attention has been on liquid delivery systems with a little work on stirrer drives. Following a general analysis of different pump types the paper describes a programmable micro-computer multi-pump unit and gives results of its use. 

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