Optimizing continuous manufacturing processes for existing batch wet granulation formulations
Creators: name: Zhou, Qiushi
Publisher: name: No Publisher Supplied
Year: 2023

description: Continuous manufacturing is a promising research area in pharmaceutical manufacturing, which improves process efficiency, agility, flexibility, and cost-effectiveness. To convert the batch process to continuous, three operation lines, including direct compaction, dry granulation, and wet granulation have been widely used. The manufacturing process usually contains a series of unit operations, such as feeding, milling, mixing, granulation, drying, and tableting. To maintain the critical quality attribute in continuous manufacturing, having a good understanding of each step of the process and optimizing the drug formulations are essential. In continuous manufacturing, powder flowability is critical. Wet granulation is a powder size enlargement process that improves powder flowability. Furthermore, it can also increase compressibility, product uniformity and enhance dissolution performance of tablets. There are different types of granulators that can be used in the continuous line, among which twin-screw granulator is the most popular choice in the industry. To achieve critical quality attributes (CQA) of the final product, the US Food and Drug Administration proposed quality by design (QbD) an approach that improves the scientific understanding of the drug process development by capturing the effect of critical material attributes (CMAs) and critical process parameters (CPPs). To improve the process understanding of twin-screw wet granulation and continuous manufacturing, this work focused on challenges that currently existed in the industry and used twin-screw granulation and continuous manufacturing to resolve them. Methodologies are first provided to convert batch wet granulation processes to continuous. Quality by design (QbD) was achieved by using statistical analysis to correlate process parameters to product quality attributes in a continuous granulation process. The resultant granules are integrated with other unit operations in the downstream processes to produce final tablets made from batch granulation, demonstrating the successful conversion from batch to continuous products with similar quality attributes. The research also found that, by adjusting excipient use in formulation, the batch wet granulation process can be converted to continuous direct compaction process. After calibrating and tunning feeders, blenders and tablet press, an end-to-end integrated continuous operation was designed. More consistent tablet uniformity than that of batch further indicated the robustness of continuous manufacturing. Then more challenging drug formulations are explored, for example, moisture, shear sensitive, and hydrophobic active pharmaceutical ingredients (APIs). These formulations reduce the success rate of twin screw granulator operation due to the high shear and liquid binder addition during the process or cause low dissolution profiles. The work demonstrated how to adjust the liquid binder use, screw configuration, and process settings to reduce the paste formation and increase robustness during the operation. By changing the excipient and combining it with twin--screw melt granulation process, the fast-release high doges' granules can be produced.