In this case study, we present an approach for employing modeling to help define the design space for a reaction with potential to generate an impurity that could impact the quality of an API. Our approach broadly consisted of (1) evaluating the reaction parameters that can affect the critical impurity level to develop appropriate assumptions for a mechanistic model, (2) developing and evaluating a mechanistic model to predict the formation of the critical impurity, (3) defining a design space based on the model output to reduce in practice the acceptable parameter space to a practical number of parameters, and (4) verifying the design space through experimental testing. This work resulted in a verified design space that can be practically employed and includes wide parameters ranges for manufacturing flexibility.

Abstract. Bilayer tableting technology has gained popularity in recent times, as bilayer tablets offer several advantages over conventional tablets. There is a dearth of knowledge on the impact of material properties and process conditions on the performance of bilayer tablets. This paper takes a statistical approach to develop a model that will determine the effect of the material properties and bilayer compression process parameters on the bonding strength and mode of breakage of bilayer tablets. Experiments were carried out at pilot scale to simulate the commercial manufacturing conditions. As part of this endeavor, a seven-factor half-fraction factorial (2 7−1 ) design was executed to study the effect of bilayer tablet compression process factors on the bonding strength of bilayer tablets. Factors studied in this work include: material properties (plastic and brittle), layer ratio, dwell time, layer sequence, first-and second-layer forces, and lubricant concentration. Bilayer tablets manufactured in this study were tested using the axial tester, as it considers both the interfacial and individual layer bonding strengths. Responses of the experiments were analyzed using PROC GLM of SAS (SAS Institute Inc, Cary, North Carolina). A model was fit using all the responses to determine the significant interactions (p<0.05). The results of this study indicated that nature of materials played a critical role on the strength of bilayer compacts and also on mode of fracture. Bilayer tablets made with brittle materials in both the layers are strongest, and fracture occurred in the first layer indicating that interface is stronger than layers. Significant interactions were observed between the selected factors and these results will provide an insight into the interplay of material properties, process parameters, and lubricant concentration on the bonding strength and mode of breakage of bilayer tablets.

Multiple stage tests are often used i n the pharmaceutical industry (e.g., content uniformity, dissolution, disintegration). Acceptance limit methodology i s given which assures t h a t a future sample will have a t least Polo chance o f passing a multiple stage test. For a given sample size, an associated acceptance region for t h e sample mean and standard deviation is found by (1) constructing a confidence region f o r the population mean and standard deviation, and (2) finding the probability o f passing t h e test f o r each population mean and standard deviation i n this confidence region. The acceptance region is the set o f all sample means and standard deviations such t h a t t h e probability of passing the test is greater than a specified P for all points in t h e confidence region.2153 Copyright 0 1990 by Marcel Dekker, Inc. Drug Dev Ind Pharm Downloaded from informahealthcare.com by University of Sydney on 01/02/15 For personal use only.

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