Tablets & Capsules


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eye on excipients 38 May/June 2021 Tablets & Capsules Kathryn Hewlett, Elizabeth Tocce, and Meinolf Brackhagen IFF Pharmaceutical manufacturing has long been defined by batch process- ing, wherein each unit operation is performed independently with a pause between each step. This methodical, time-tested approach has been used for decades. But a better method is on the horizon, and other industries that produce and process materials on a massive scale have already made the jump. Industries as diverse as petrochemicals, polymers, and food production have transitioned from batch to continuous processing tech- nologies in manufacturing, driven by cost and quality considerations. The pharmaceutical industry looks to follow in the footsteps of these industries, backing away from the slow-but-steady pace of batch processing toward a future of con- tinuous manufacturing (CM). Drug developers have much to gain—with CM in place, they can save time, reduce human error, improve quality, and respond more nimbly to market changes. Additionally, the industry as a whole expects to meet increas- ing demand and keep drug shortages in check. This promising new method is not without barriers to entry. One potential drawback of CM includes high start-up costs related to equip- ment—more specifically, retiring the old and purchasing the new. Technicians must be trained, infra- structure revamped, and adequate analytical technology developed to enable the real-time monitoring that CM provides. And on top of all these upfront costs of time and capital, CM finds itself mired in the percep- tion of regulatory uncertainty. Challenges aside, many of the industry's most prestigious institu- tions—including the FDA—hold the view that CM can help prevent shortages, improve risk management, mitigate prescription drug quality concerns, and meet the rising tide of demand. So, what stands in the way of pharma's adoption of such a seem- ingly obvious solution? One of the biggest problems we can pinpoint is a knowledge gap around the impact of excipients. Knowing which ones to choose and which to avoid can mean the difference between smooth oper- ations and constant manufacturing headaches. As it turns out, material properties, including those of excip- ients, are critical to CM performance. Failure modes at a glance Excipients can impact a continuous process in myriad ways. When that impact skews negative, the result- ing problem on the manufacturing line is called a "failure mode." The most common of these failure modes include segregation, packing, friction, and attrition, all of which affect pow- der flow. Some failure modes are not inherently problematic, but all must be accounted for when developing a continuous process and formulation to ensure an optimal end product. Segregation affects both physical properties and product quality. Along the manufacturing line, powders tend to segregate by particle size upon exposure to external forces such as shear. A major discrepancy in parti- cle size throughout a formulation can cause issues with content uniformity. Packing during processing can lead to a change in formulation density. Put simply, small particles can fill the interstitial spaces left between large particles, often resulting in an undesir- able change in bulk density. Changes in packing or bulk density within the production line reduces material flow, which can lead to reduced through- put or even a complete shutdown. Friction impacts mechanical stability and flowability. When par- ticles are subjected to large amounts of friction, such as through shear, it may result in a change in particle morphology or size. Attrition refers to a change in particle size caused by breakage, where larger pieces of par- ticles break off as irregularities from the particle surface are smoothed over. Both friction and attrition can impact formulation performance as the surface area and interaction between particles changes. The right stuff for every step Evaluating the material properties of excipients to use in CM presents a bit of a moving target, as the demands on excipients may change at different stages of a continuous process. For example, at the feeding and blending stage, there is often debate about the importance of powder flow. Since much of the equipment used in CM has been designed to handle a broad range of materials, powder flow diminishes in importance once mate- rial is inside the system. However, an ideal excipient should be able to

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