II

Figure 6.52. Data arrangement and blocking of variables for process stages and phases.

models can be used to eliminate major disturbances in future batches, and therefore to help adjust control limits for more consistent production, which is crucial for pharmaceutical production processes [604].

Stage 1 is the wet granulation of the fine powder mix of active ingredients) and other pharmaceutical excipients. The objective of the granulation is to increase the particle size by agglomerating this fine powder by adding a binder solution under continuous mixing. Particle size increase promotes higher bioavailability of the drug. At this stage, the amount of binder used and its addition rate are effective on the particle size increase. The amount of binder solution and its addition rate are predefined based on experimental design studies. We have assumed a fixed total amount of binder solution in the simulation studies. Binder addition rate, impeller speed, and power consumption are taken as measured process variables at this stage. Stage 1 is operated in two phases: phase 1, dry mixing for a fixed time interval, and phase 2, binder addition while mixing (Fig. 6.53). Since there are small fluctuations in binder flow rate at each batch, the final time of the second phase is variable, producing unequal batch length for stage 1. These differences should be eliminated prior to multivariate statistical modeling. To equalize data lengths in phase b

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