Scale-up changes

The parameters selected should be appropriate for the process, in those cases where the manufacturing process has been controlled and validated as specified in the foregoing discussion, batch scale-up, changes in site of manufacture, allowance for equipment change (where the operating principle is the same), minor formulation changes, etc., should be determined on the basis of the comparability of both the blend/granulation and the final product as assured by (1) appropriate tests, (2) specifications, (3) process validation, and (4) comparative accelerated stability . 

Changes in Batch Size Postapproval changes in the size of a batch from the pilot scale used to manufacture product for clinical trials to larger or smaller commercial batch sizes require submission of additional information in the apphcation. Scale-down below 100,000 dosage units is not covered by this guidance. All scale-up changes should be properly validated and, where needed, inspected by appropriate FDA personnel. 

Recently the FDA, with the cooperation of the Pharmaceutical Industry has developed a series of guidance procedures to speed approval of post approval changes with or without process scale-up changes. At the present time the SUPAC (scale-up post approval change) program covers the following product categories ... 

The profile of impurities in a new drug substance may change for a variety of reasons, such as process scale-up changes, synthetic route changes, and changes made to key intermediates. ICH decision trees help classify, qualify, and select limits for new molecular entities (NMEs). If an impurity exceeds the qualification threshold listed below in Table 3 (ICFI Q3A(R)), studies are needed to qualify that impurity in drug substances. 

The change in interaction energy per 1,2 pair is thus h. Aw. Next we must consider how this scales up for a large array of molecules, and particularly how to describe the concentration dependence of the result. 

When choosing the scale-up method, changes in other flow/power parameters and their impact on the process result must be considered. Figure 11 shows changes in important parameters for different scale-up bases. For example, scale-up based on same tip speed maintains the T / Ubut decreases P/ Uby 80%. T / Uis almost always increased on scale-up. Scale-up based on the same P/ Umeans a reduction in mixer speed by 66%, which also... 

Fig. 11. Changes ia mixing parameters on scale-up to 125 times the volume of the pilot plant.

The production of elfamycins is described in the references cited in Table 1. Fermentation yield improvements with aurodox (1, R = CH ) proved difficult because of feedback inhibition (48). Aurodox-resistant strains (49), however, responded positively to conventional mutagenic methods leading to yield increases from 0.4 to 2.5 g/L (50). Scale-up of efrotomycin (7, R = CH ) fermentations were found to be particularly sensitive to small changes in sterilization conditions of the oil-containing medium used (51). 

Incorrect/incom- Review material of construction requirements vs. patible materials existing equipment before changing service of construction, corrosion coupons during pilot/develop-used in transfer- ment/scale-up ring/charging line or equipment. CCPS G-23... 

A client may choose to develop a toller who is qualified, but will need additional or improved equipment and technology to meet the eventual production levels required later in the life of the toll contract. The client may require the toller to make changes or modifications at their plant in order to effectively manufacture a particular product in increasing quantity. Some areas of concern applicable to scale up were listed in Various Points to Consider, Section 3.1. Additional considerations to address in the contract may include ... 

Study. Their location represents the range of the conditions that should be used in a statistically designed set of experiments for kinetic studies and not actual conditions at the particular location. This way, the same flow is again maintained on all three scales and the troublesome effect of changing flow conditions on scale-up can be eliminated. The proposed idea, for scale-up by scale-down from the view point of the catalyst, was proven to be effective in many industrial projects. 

The influence of transport process in two-phase reaction systems depends on flow conditions, which change with the size of the equipment. This is the reason for the historic observation that performance changes as processes are scaled up and therefore scale-up should be done in several steps, each limited to a small increase in size. This is a slow and expensive method and still does not guarantee optimum design. 

The scale-up of exothermic processes is greatly enhanced through the use of the coefficient of thermal stability. Kafarov [2] defined this as the ratio of the slope (tan ttj) of the line representing the heat removal (due to the heat transfer medium and changes in enthalpy) to the slope (tan ttj) of the line representing heat generation (by the reaction) at the intersection of the two lines when plotted on the T versus Q coordinates. This is expressed as... 

The conventional scale-up criteria scale-up with constant stirrer speed , scale-up with constant tip speed and scale-up with constant specific energy input are all based on the assumption that only one mixing process is limiting. If, for example, the specific energy input is kept constant with scale-up, the same micromixing behaviour could be expected on different scales. The mesomixing time, however, will change with scale-up as a result, the kinetic rates and particle properties will be different and scale-up will fail. 

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