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16 Pharmaceutical Technology ® Trends in Formulation eBook September 2024 PharmTech.com E xcipiEnts highly compressible materials, this can lead to bridges and densif ication in the screws, ulti- mately negatively impacting mass f low variabil- ity. Refill limits and charging systems (manual vs. pneumatic, for example) should be designed with material compressibility in mind. • Moisture content impacts blend hold time (po- tential for microbiological contamination), pow- der f lowability, tribocharging, tableting proper- ties, and drug product stability. Characterization technique considerations. Per- formance-related properties—the physical character- istics of excipients that may impact performance and drug product manufacturability—are generally not comparable due to multiple, non-standardized meth- ods. Formulators are then required to test these as part of product development and include the results in risk assessments and regulatory submissions that contain the product knowledge and history. For example, particle size distribution can be de- termined by laser diffraction or sieve analysis, and other techniques. Flowability can be described based on Hausner Ratio, Carr's Index, Angle of Repose, or powder rheometry. Considering that there are multi- ple ways to test an attribute, the details of the method are as important as the results to allow comparability. Having standardized methods offer several bene- fits: • Dat a compa rabi l it y enables con sistent com- parison of data across different labs, sites, and batches. • Enhanced process control—if methods are stan- dardized, sites can share a raw material database with known interactions with their unit oper- ations (process performance) and dr ug prod- uct quality. This would allow for a prediction of process and product robustness, such that precise adjustments to process parameters like refill limits and blending speeds can be tuned based on factors like compressibility and f low- ability. This ensures consistent product quality throughout continuous production. • Improved communication and collaboration— standardized data creates a common language for communication among scientists, engineers, and regulators. This can allow for faster tech- nology and product transfer amongst company sites, and clear communication from the user to the excipient supplier and vice versa in cases of investigations. • Reduced costs and risk s—accurate and com- parable data minimizes the need for extensive re-testing and troubleshooting, leading to cost and full-time equivalent (FTE) savings, and re- duced risk of production delays associated with inconsistency in raw material behavior. The successful implementation of CM in the phar- maceutical industry relies heavily on the reliable as- sessment of raw materials—both excipients and API. Inconsistency in raw material properties can have a domino effect, impacting process stability, product quality, and ultimately, patient safety. Standardizing characterization techniques can mitigate these risks and ensure successful CM implementation. Impact of material properties and variability on continuous manufacturing To understand excipient variability, it might be help- ful to understand several factors. Excipients, partic- ularly those that are naturally derived or quarried and refined, of ten have complex multicomponent compositions. Changes in seasonal growing condi- tions, for example, may result in varying composition, even if only slight, which could impact physical and/ or functional properties. Unlike many pharmaceuti- cal products, excipients are sometimes manufactured on a metric ton scale, often by CM. This leads not only to batch-to-batch variabilit y (inter-batch variabil- ity), which is often monitored, but also excipient in- tra-batch variability, or package-to-package variabil- ity. While a well-designed, robust continuous process for drug product can manage excipient variation that might otherwise adversely affect process, product quality, or performance, understanding slight vari- ations within an excipient (or API) batch can assist in designing a robust CM process. Raw material properties, both physical and func- tional, can impact process behavior due to the par- ticle–particle interactions taking place throughout the equipment train. Using a quality-by-design (QbD) approach to understand material attributes and their impact on the process and product can facilitate better product robustness. Individual ingredients should be characterized for their intended role in a formulation in addition to how the interactions among ingredients impact the CM process and product quality. For exam- ple, understanding segregation tendency during man- ufacture may help with ingredient selection before moving forward with process design. By understand- ing the critical material attributes, and modeling one or more continuous process designs, the best outcome can be achieved. Excipient variability can also lead to changes in the PAT signal and consequent analysis. PAT feedback is critical in implementing an adequate control strategy and ensuring a robust CM process. Without a defined control strategy with PAT input, process drift could lead to product or process failure, affecting yield. As- sessing the effect of material changes on residence time distributions and from there on, establishing actionable system responses to disturbances are key to ensuring consistent product quality and process