Quality by Design Procedure for Continuous Pharmaceutical Manufacturing: An Integrated Flowsheet Model Approach

Pharmaceutical manufacturing is crucial to global healthcare and requires a higher, more consistent level of quality than any other industry. Yet, the traditional pharmaceutical batch manufacturing has remained largely unchanged in the last fifty years due to high R&D costs, shorter patent durations, and regulatory uncertainty. This has led regulatory bodies to promote modernization of manufacturing process to continuous pharmaceutical manufacturing (CPM) by introducing new methodologies including quality by design, design space, and process analytical technology (PAT). This represents a shift away from the traditional pharmaceutical manufacturing way of thinking towards a risk based approach that promotes increased product and process knowledge through a data-rich environment. While both literature and regulatory bodies acknowledge the need for modernization, manufacturers have been slow to modernize due to uncertainty and lack of confidence in the applications of these methodologies. This paper aims to describe the current applications of QbD principles in literature and the current regulatory environment to identify gaps in literature through leveraging regulatory guidelines and CPM literature. To aid in closing the gap between QbD theory and QbD application, a QbD algorithm for CPM using an integrated flowsheet models is also developed and analyzed. This will help to increase manufacturing confidence in CPM by providing answers to questions about the CPM business case, applications of QbD tools, process validation and sensitivity, and process and equipment characteristics. An integrated flowsheet model will aid in the decision-making process and process optimization, breaking away from ex silico methods extensively covered in literature

Model-Based Tools for Pharmaceutical Manufacturing Processes

The Special Issue on “Model-Based Tools for Pharmaceutical Manufacturing Processes” will curate novel advances in the development and application of model-based tools to address ever-present challenges of the traditional pharmaceutical manufacturing practice as well as new trends. This book provides a collection of nine papers on original advances in the model-based process unit, system-level, quality-by-design under uncertainty, and decision-making applications of pharmaceutical manufacturing processes

Investigating the Trade-Off between Design and Operational Flexibility in Continuous Manufacturing of Pharmaceutical Tablets: A Case Study of the Fluid Bed Dryer

Market globalisation, shortened patent lifetimes and the ongoing shift towards personalised medicines exert unprecedented pressure on the pharmaceutical industry. In the push for continuous pharmaceutical manufacturing, processes need to be shown to be agile and robust enough to handle variations with respect to product demands and operating conditions. In this paper we examine the use of operational envelopes to study the trade-off between the design and operational flexibility of the fluid bed dryer at the heart of a tablet manufacturing process. The operating flexibility of this unit is key to the flexibility of the full process and its supply chain. The methodology shows that for the fluid bed dryer case study there is significant effect on flexibility of the process at different drying times with the optimal obtained at 700 s. The flexibility is not affected by the change in volumetric flowrate, but only by the change in temperature. Here the method used a black box model to show how it could be done without access to the full model equation set, as this often needs to be the case in commercial settings

Technoeconomic Evaluation of Multiple Mixed Suspension-Mixed Product Removal (MSMPR) Crystallizer Configurations for Continuous Cyclosporine Crystallization

Continuous crystallization using Mixed Suspension-Mixed Product Removal (MSMPR) crystallizers has been demonstrated as a feasible method for implementing continuous separations in pharmaceutical manufacturing processes. This work conducts a steady-state process modeling and simulation study of the continuous cooling crystallization of cyclosporine, comparing processes with and without solids recycle for their technoeconomic viability. The model describes population balance equations, crystallization kinetics, and process mass balances to compare attainable crystallization and plantwide yields of different process configurations. Total cost components using an established economic analysis methodology are compared for varying numbers of crystallizers, operating temperatures, total crystallizer cascade residence times and API feed concentrations. Economic analyses and the calculation of normalized cost components with respect to total crystallizer volumes identify the process without recycle as the most economically viable option, achieving the lowest total costs and low <i>E</i>-factors for pharmaceutical processes. The sensitivity of total costs to the selected total residence times for economic analyses highlights the need for rigorous comparison methodologies. This work identifies the need for technoeconomic optimization studies of continuous crystallization processes to establish the optimal design of manufacturing campaigns prior to further development