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14 Pharmaceutical Technology ® Trends in Formulation eBook September 2024 PharmTech.com E xcipiEnts ensure success in the development and manufacture of pharmaceutical products through continuous pro- cesses. One example is International Pharmaceutical Excipients Council of the Americas (IPEC-Americas) and how the various IPEC guides may assist in under- standing the role of excipients in CM. CM is also gaining traction in the manufacture of biologic drug substances and their dosage forms. Many biologics are liquids intended for injection and excipient considerations for CM of liquid biologic drugs are quite different than for OSDs. This article will focus on CM for OSDs. Material property impact on CM processes CM offers efficiency, cost-effectiveness, and real-time quality control in a reduced footprint compared to traditional batch manufacturing. However, this shift from batch-based to continuous production hinges on one critical factor: understanding and controlling the material properties of the raw materials involved. A growing body of knowledge is being developed on this topic for CM of liquids, semisolids, and OSDs. The majority of FDA- and European Medicines Agency (EMA)-approved commercial CM drug products are OSDs, particularly tablets, manufactured via direct compression or twin-screw granulation platforms. The following sections focus on highlighting the importance of characterizing raw materials and un- derstanding their variability for manufacture of OSDs. General considerations based on unit operations and specific case studies are provided. Why are material properties so important? The impact of raw material properties on process perfor- mance and drug product quality has been extensively studied. Understanding this impact does not auto- matically translate to robust processes and products. Control strategies to accommodate the impact of raw material variability should minimize the number of alarms and process interruptions and give robustness and consistent product quality. For continuous manufacturing of OSDs, the fol- lowing are three major reasons why it is important to proactively evaluate the impact of raw material properties: • Product quality: Variations in material proper- ties can impact product critical quality attributes (CQAs) such as drug release, potency, and ulti- mately, patient safety. • Process robustness and consistenc y: Predict- able material properties reduce the risk of mass flow deviations from their set point, minimizing alarms and process downtime, and maximizing process and process ana ly tica l technologies (PAT) model robustness. Robust models require less updates and, if used for real-time release, reduce downtime and supply chain disruptions. • Process/platform optimization: Tailoring pro- cess parameters based on material properties (e.g., via design spaces) can improve efficiency, yield, and overall cost-effectiveness (faster re- turn on investment [ROI]) of the manufacturing platform. Powder properties that impact unit operations in CM. CM, when optimized, allows for enhanced pre- dictability and control. Understanding the impact of raw material variability on process performance will allow for the design of a control strategy that ensures continual high drug product quality. A com- prehensive list of all the material properties that can impact formulation and process development of liq- uids, creams, gels, and OSDs, is outside of the scope of this article. To date, most CM approvals have been for OSDs. The following is a list of the material properties to consider for manufacturing pharmaceutical tablets or capsules: • Particle size distribution can impact f lowability, cohesion, mixing dynamics, blending time, and granulation torque. • Bulk density needs to be considered in feeder de- sign. Light, f luffy powders are more difficult to feed and compress, and may require pre-blend- ing steps before incorporation in a continuous process line. • Surface area and mor pholog y proper ties can inf luence electrostatics or tribocharging, tablet ejection force, drug dissolution, and film coating effectiveness. • Flowabilit y and cohesiveness (inverse correla- tion) determine powder handling, feeding config- urations, mass flow alarms and noise/smoothing averages, blending efficiency, pre-compression pa ra meters, a nd ot hers. A sh if t in excipient or API cohesion can impact its f lowability and thus how efficiently it fills screw f lights. These differences can require new feed factor calibra- tions (grams delivered per revolution) and con- trol parameter tuning on screw speed to reach the mass f low setpoints. Additionally, poor f lowing blends can introduce increased tablet and capsule weight variability and thus impact overall assay. Paradoxically, a free-f lowing blend can also seg- regate more easily as it moves downstream to the tablet press or capsule machine and flood the dies wherein increased tablet weight variability is the system response. • Compressibility refers to changes in powder vol- ume as an effect of applied normal force. Excip- ients with higher compressibility are generally more cohesive (they can function as binders) and are sensitive to shear. Increased head pressure when charging material into the feeder hopper (refill) will increase powder packing and, for