Building blocks of continuous pharmaceutical manufacturing
Creators: name: Keyvan, Golshid
Publisher: name: No Publisher Supplied
Year: 2020

description: Continuous manufacturing (CM) is gaining popularity within the pharmaceutical industry as it is undergoing a shift from the conventional batch manufacturing of the last century to a new continuous paradigm that greatly enables use of advanced manufacturing methods. Continuous manufacturing offers many advantages such as flexibility, quality, robustness, higher yield, and lower manufacturing costs. Although CM is common in other industries (e.g., food and chemicals), it is an emerging technology in the pharmaceutical industry. Undoubtedly, continuous processing lends itself to in-process monitoring and closed-loop control. Process understanding, control strategies, and on-line, in-line, or at-line measurements of critical quality attributes provide for control strategies that include real- time quality evaluation of products. Under CM, real-time product quality assurance has been widely investigated under the Quality-by-Design (QbD) guidelines recommended by the FDA to advance the pathway to Real Time Release testing (RTRt). Solid oral dosage products such as tablets and capsules constitute about 60% of global drug prescriptions, and their critical quality attributes (CQAs) such as hardness and dissolution, are well defined. Historically, they have been manufactured using batch methods and quality is evaluated by extracting a small number of samples that are subsequently subjected to destructive testing to evaluate quality. More recently, as the result of continuous processing, there is a movement away from end-of-line sample testing towards the adoption of in-process measurement strategies that ensure product quality in real-time. The first step in implementing an in-process test methodology towards RTRt is to identify the critical steps in the manufacturing processes, understand their failure modes, and develop design methodologies to prevent them from defeating the process. In this work, we examined building blocks of two continuous manufacturing processes; DCCM (Direct Compression Continuous Manufacturing) and CHME (Continuous Hot Melt Extrusion). In both operations, we identified the critical processing parameters so that it could lead to implementing in-process testing methodologies that would enable RTRt. We characterized the process and examined the interplay between the process parameters and the product quality. This was accomplished by executing designed experiments on both processes and characterizing the tablets in terms of their critical quality attributes (CQAs) such as dissolution and hardness. Furthermore, we found a correlation between the tensile strength and dissolution of the continuously manufactured tablets and the processing parameters in the manufacturing line that can predict process performance. The predictive approach will not only enable us to develop a control strategy to determine the process parameters values that keep the process within the control space but also facilitate development of new solid oral dose products in the event of an emergency or drug shortages.