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Tablets & Capsules April 2015 19 Fischer designs. The rabbit-ear baffles provide gentle mixing and are suitable for friable tablets, but their mix- ing efficiency is poor. Tubular baffles provide good mix- ing of round tablets but have limitations when it comes to friable tablets and tablets of other shapes. Fischer and spi- ral baffles are more useful overall since they provide gen- tle and efficient mixing and handle all tablet shapes and sizes. Spray nozzles. Two basic types of nozzles are avail- able: the horn design and the anti-bearding design. A major disadvantage of horn-type nozzles is that spray- dried coating (dust) deposits on the air cap, causing clogs and disturbing the spray pattern. As a result, many manu- facturers favor anti-bearding caps, some of which include a self-cleaning provision. Airflow pattern. The turbulence from the hot air in the process zone—the airflow pattern—varies from man- ufacturer to manufacturer. The most common and tradi- tional is diagonal flow, with the air entering at the cham- ber's top and exiting at a diagonal through an exhaust shoe at the bottom. This pattern causes the hot air to pass through the coating zone, which leads to spray dry- ing and formation of a beard on the nozzle, eventually reducing coating efficiency. The diagonal pattern also disturbs the spray pattern, leading to non-uniform coat- ing. In other flow patterns, including the within-bed and horizontal, the path of hot air is separated from the spray zone, which eliminates spray drying and thus minimizes the chance of spray-pattern deviations. This leads to a more consistent and uniform distribution of the API on the tablets. In addition to these design factors, the coating system must offer a means to control—as Quality by Design (QbD) requires—all the critical parameters (airflow, tem- perature, differential pressure, spray rate, atomization pressure, etc.) within a specified range at all times. This is often done through automation. Key process parameters It is important to understand the critical process vari- ables and how they interact when layering an API onto tablets because they directly affect the assay and content uniformity of the final unit dose. First, examine the coat- ing uniformity by determining the assay value of the coated tablets. According to USP guidelines, API varia- tion must not exceed 6 percent relative standard devia- tion (RSD) [3]. Variation is of two types once the process reaches the commercial stage: batch-to-batch and tablet-to-tablet. In some cases, manufacturers analyze the batch for the assay and, if required, perform additional coating to save the batch. But that practice is not acceptable to many manu- facturers or regulators, who insist on a robust process that ensures the product meets the specification on the first attempt. Another major challenge is achieving content uniformity across the batch. There have been many instances of batch failures due to a high RSD value of intra-tablet assay, in which case the batch had to be dis- carded. Such cases raise a question about the robustness of the manufacturing process for the particular product. If the out-of-spec assay goes undetected, it could lead to a market recall that would damage the brand and entail a severe financial loss. Case study This article discusses how to identify and optimize the critical process parameters (CPPs) using a QbD approach. The first step was to conduct a risk assessment to select the process parameters that had the most effect on the product's critical quality attributes (CQAs). A 24 full factorial design was employed as a statistical model to optimize the process variables, which included pan speed, spray rate, atomizing-air pressure, and nozzle-to- bed distance. Paracetamol (acetamino phen) was selected as the model API. Numerical and graphical optimization techniques that employed a design-space approach were used to understand the critical process and machine para- meters by setting a constraint on the dependent and independent variables. The results revealed the interaction of the parameters and highlighted the CPPs that were critical to monitor when layering an API onto to tablets using a perforated pan coater. The experimental values of percentage assay and RSD of content uniformity for an optimized batch were found to be in close agreement with those predicted by the mathematical model, thus confirming the validity of the coating process. Materials and methods Formulating the tablet using layering. Placebo gran- ules comprising mainly starch and lactose were manufac- tured using a top-spray granulation technique with PVP K30 as a binder. The granules were compressed into tablets using a 9-millimeter round, standard punch. The tablets, which would serve as the substrate for API layer- ing, were seal-coated to 2 percent weight gain using HPMC E5. The model API, paracetamol, was combined with HPMC E5 (binder) and PEG 6000 (plasticizer). Table 1 lists the composition of the API coating solution. Risk assessment of CQAs. The ICH Q9 guidance outlines the concept of quality risk management in terms of assessing, controlling, communicating, and reviewing the risks to the "quality target product profile" (QTPP) over a product's lifecycle, and optimization of the coating process was critical to the QTPP. The risk assessment for Table 1 Composition of layering solution Ingredient Milligrams per tablet Paracetamol 9.8 HMPC 5.0 PEG 6000 1.6 Ethanol and purified water (30:70) As needed to 12% Total weight of API-layered tablet 322.4