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

Resilience and risk analysis of fault-tolerant control design in continuous pharmaceutical manufacturing

PresentationThe effects of the paradigm shift from batch to continuous manufacturing on pharmaceutical industry, in terms of process safety and product quality, e.g., danger of dust explosions and risk of off-spec products, are of major concerns in the recent research progress in control system design. Specifically, a fault-tolerant control of critical process parameters (CPPs) and critical quality attributes (CQAs) is of paramount importance for the continuous operation with built-in safety and quality. In this study, a systematic framework for fault-tolerant control design, analysis, and evaluation for continuous pharmaceutical solid-dosage manufacturing is proposed, consisting of system identification, control design and analysis (controllability, stability, resilience, etc.), hierarchical three-layer control structures (model predictive control, state estimation, data reconciliation, etc.), risk mapping, assessment and planning (Risk MAP) strategies, and control performance evaluation. The key idea of the proposed framework is to identify the potential risks in the control design, material variance, and process uncertainties, under which the control strategies are evaluated. The framework is applied to a continuous direct compaction process, specifically the feeding-blending system wherein the major source of variance in the process operation and product quality arises. It can be demonstrated that the process operation failures and product quality variances in the feeding-blending system can be mitigated and managed through the proposed systematic fault-tolerant control system design and risk analysis framework

Flowsheet simulation of solids processes: Current status and future trends

Complex manufacturing processes are nowadays applied for production of various solid products. It is very common that for production of particles with desired properties several transformation steps like drying, milling, classification, granulation, etc. should be involved. This leads to the process structures consisting of different apparatuses or transformation substeps connected with material and energy balances. Consequently, development of new processes or optimization of already existing, as well as an optimal control, is a very challenging task, which can be partially solved using numerical modelling. For the simulation of modern production processes, the flowsheet calculations can be effectively used. Starting from the 80 s a lot of work focused on the flowsheet simulation of liquid-vapor systems has been done and as result various well-established systems exist today. With respect to the solid processes the intensive research has been started much later. In this contribution we present our view about a current role of flowsheet simulation for modeling of particulate materials and specify the open fields which can be covered in future research

Quality Control Perspectives during Mass Production with a Focus on the Chemical Industry

Mass production was part of the industrial revolution in 1870 and, with it, a huge step change in manufacturing processes. Its impact was ground breaking and became even more remarkable with automation in a business production environment. The chemical industry is one of the manufacturing sectors that has benefited from the technology of mass production achieved through automating the business process. In this era of industry 4.0 and with the associated advanced technologies of smart manufacturing, cloud computing, cyber physical systems and internet of things, mass production has been revolutionised but still faced issues such as quality control of the production process which was affected by supply chain management, customised production of commodity and specialty chemicals and huge demand from other chemical industry manufacturers. This chapter has reviewed the evolution of mass production during traditional manufacturing to the present day and carried out a risk assessment to quality of production in a mass production environment with a view to recommending adequate quality control of the production process. The chapter also included a case study for mass production of a pharmaceutical drug—Amoxicillin which was partly batch produced into dry powder and then mass produced using tableting and encapsulating machine, highlighting sources of contamination and inconsistency in tablet weight if adequate control measures were not put in place

Modeling, optimization, and sensitivity analysis of a continuous multi-segment crystallizer for production of active pharmaceutical ingredients

We have investigated the simulation-based, steady-state optimization of a new type of crystallizer for the production of pharmaceuticals. The multi-segment, multi-addition plug-flow crystallizer (MSMA-PFC) offers better control over supersaturation in one dimension compared to a batch or stirred-tank crystallizer. Through use of a population balance framework, we have written the governing model equations of population balance and mass balance on the crystallizer segments. The solution of these equations was accomplished through either the method of moments or the finite volume method. The goal was to optimize the performance of the crystallizer with respect to certain quantities, such as maximizing the mean crystal size, minimizing the coefficient of variation, or minimizing the sum of the squared errors when attempting to hit a target distribution. Such optimizations are all highly nonconvex, necessitating the use of the genetic algorithm. Our results for the optimization of a process for crystallizing flufenamic acid showed improvement in crystal size over prior literature results. Through the use of a novel simultaneous design and control (SDC) methodology, we have further optimized the flowrates and crystallizer geometry in tandem.^ We have further investigated the robustness of this process and observe significant sensitivity to error in antisolvent flowrate, as well as the kinetic parameters of crystallization. We have lastly performed a parametric study on the use of the MSMA-PFC for in-situ dissolution of fine crystals back into solution. Fine crystals are a known processing difficulty in drug manufacture, thus motivating the development of a process that can eliminate them efficiently. Prior results for cooling crystallization indicated this to be possible. However, our results show little to no dissolution is used after optimizing the crystallizer, indicating the negative impact of adding pure solvent to the process (reduced concentration via dilution, and decreased residence time) outweighs the positive benefits of dissolving fines. The prior results for cooling crystallization did not possess this coupling between flowrate, residence time, and concentration, thus making fines dissolution significantly more beneficial for that process. We conclude that the success observed in hitting the target distribution has more to do with using multiple segments and having finer control over supersaturation than with the ability to go below solubility. Our results showed that excessive nucleation still overwhelms the MSMA-PFC for in-situ fines dissolution when nucleation is too high