Maitraye Sen

Computer-Aided Flowsheet Simulation of a Pharmaceutical Tablet Manufacturing Process Incorporating Wet Granulation

In this work, a dynamic flowsheet model for the production of pharmaceutical tablets through a continuous wet granulation process is developed. The unit operation models which are integrated to compose the process line form a hybrid configuration which is comprised of a combination of mechanistic models, population balance models, and empirical correlations, based on the currently available process knowledge for each individual component. The main objective of this study is to provide guidance in terms of the necessary steps which are required in order to move from the unit operation level to the simulation of an integrated continuous plant operation. Through this approach, not only significant process conditions for each individual process are identified but also crucial interconnecting parameters which affect critical material properties of the processed powder stream are distinguished. Through the integration of the dynamic flowsheet with a final component of tablet dissolution, the connection of the processing history of a set of powders which undergo wet granulation and are contained in each produced tablet to the release rate of the pharmaceutical ingredient is enabled. The developed flowsheet is used for the simulation of different operating scenarios and disturbances which are often encountered during operation for the assessment of their effects towards critical material attributes, product properties, and the operation of further downstream processes. Simulation results demonstrate that granulation and milling which control the particle size distribution of the processed powder mixture highly affect the hardness and dissolution of the produced tablets.

Mathematical Development and Comparison of a Hybrid PBM-DEM Description of a Continuous Powder Mixing Process

This paper describes the development of a multidimensional population balance model (PBM) which can account for the dynamics of a continuous powder mixing/blending process. The PBM can incorporate the important design and process conditions and determine their effects on the various critical quality attributes (CQAs) accordingly. The important parameters considered in this study are blender dimensions and presence of noise in the inlet streams. The blender dynamics have been captured in terms of composition of the ingredients, (relative standard deviation) RSD, and (residence time distribution) RTD. PBM interacts with discrete element modeling (DEM) via one-way coupling which forms a basic framework for hybrid modeling. The results thus obtained have been compared against a full DEM simulation which is a more fundamental particle-level model that elucidates the dynamics of the mixing process. Results show good qualitative agreement which lends credence to the use of coupled PBM as an effective tool in control and optimization of mixing process due to its relatively fewer computational requirements compared to DEM.

Multi-scale flowsheet simulation of an integrated continuous purification–downstream pharmaceutical manufacturing process

Properties of active pharmaceutical ingredients influence the critical quality attributes (CQAs) of final solid dosage forms (e.g. tablets). In the last decade, continuous manufacturing has been shown to be a promising alternative to batch processing in the pharmaceutical industry. Therefore, a quantitative model-based analysis of the influence of upstream API properties on downstream processing quality metrics will lead to enhanced QbD in pharmaceutical drug product manufacturing (Benyahia et al., 2012). In this study, a dynamic flowsheet simulation of an integrated API purification step (crystallization), followed by filtration and drying, with a downstream process (powder mixing) is presented. Results show that the temperature profile of a cooling crystallization process influences the crystal size distribution which in turn impacts the RSD and API concentration of the powder mixing process, which in turn has a direct effect on tablet properties (Boukouvala et al., 2012). A hybrid PBM-DEM model is also presented to demonstrate the coupling of particle-scale information with process-scale information leading to enhanced elucidation of the dynamics of the overall flowsheet simulation.

Closed-Loop Feedback Control of a Continuous Pharmaceutical Tablet Manufacturing Process via Wet Granulation

The wet granulation route of tablet manufacturing in a pharmaceutical manufacturing process is very common due to its numerous processing advantages such as enhanced powder flow and decreased segregation. However, this route is still operated in batch mode with little (if any) usage of an automatic control system. Tablet manufacturing via wet granulation, integrated with online/inline real time sensors and coupled with an automatic feedback control system, is highly desired for the transition of the pharmaceutical industry toward quality by design as opposed to quality by testing. In this manuscript, an efficient, plant-wide control strategy for an integrated continuous pharmaceutical tablet manufacturing process via wet granulation has been designed in silico. An effective controller parameter tuning strategy involving an integral of time absolute error method coupled with an optimization strategy has been used. The designed control system has been implemented in a flowsheet model that was simulated in gPROMS (Process System Enterprise) to evaluate its performance. The ability of the control system to reject the unknown disturbances and track the set point has been analyzed. Advanced techniques such as anti-windup and scale-up factor have been used to improve controller performance. Results demonstrate enhanced achievement of critical quality attributes under closed-loop operation, thus illustrating the potential of closed-loop feedback control in improving pharmaceutical tablet manufacturing operations.

Integrated Moving Horizon-Based Dynamic Real-Time Optimization and Hybrid MPC-PID Control of a Direct Compaction Continuous Tablet Manufacturing Process

In this manuscript, a moving horizon-based real-time optimization (MH-RTO) has been integrated with a hybrid model predictive control (MPC) system for a continuous tablet manufacturing process for quality by design (QbD)-based efficient continuous manufacturing. In the proposed approach, the integrated MH-RTO provides the optimal operational set points for the tablet production rate in real time. The MH-RTO takes into consideration the capital and operating cost, the market fluctuations, the product inventory, the product quality assurance strategy, the regulatory constraints, and the product rejections. An advanced hybrid model predictive control system then ensures that the required production rate with desired quality is met with minimum resources and time. A robust optimization strategy and an efficient control system have been integrated to achieve the maximum profit. The MH-RTO integrated with a hybrid control strategy ensures the maximum possible profit irrespective of the market demand fluctuations. The basic advantage of the MH-RTO framework is that it takes into consideration the future demand and thus can lead to increased profit compared to a standard real-time optimization approach.

Simulation-Based Design of an Efficient Control System for the Continuous Purification and Processing of Active Pharmaceutical Ingredients

In this study, an efficient system-wide controlsystem has been designed for the integrated continuous purification and processing of the active pharmaceutical ingredient (API). The control strategy is based on the regulatory PID controller which is most widely used in the manufacturing industry because of its simplicity and robustness. The designed control system consists of single and cascade (nested) control loops. The control system has been simulated in gPROMSTM (Process System Enterprise). The ability of the control system to track the specified set point changes as well as to reject disturbances has been evaluated. Results demonstrate that the model shows an enhanced performance in the presence of random disturbances under closed-loop control compared to an open-loop operation. The control system is also able to track the set point changes effectively. This proves that closed-loop feedback control can be used in improving pharmaceutical manufacturing operations based on the Quality by Design (QbD) paradigm.

Population Balance Models for Pharmaceutical Processes

The pharmaceutical industry is predominantly dominated by the handling of particulate matter in the form of solids and emulsions. With the enforcement of the Quality by Design (QbD) initiative by the Food and Drug Association (FDA), a process systems engineering based case toward particulate process design is advantageous. This suggests the need for mechanistic modeling approaches that can be used for an accurate representation of the process dynamics. The inherent discrete nature of population balance models (PBM) makes it an appropriate framework for modeling particulate processes. With the representation of the particulate processes used for pharmaceutical product manufacturing using various modeling frameworks, advancements can be made to improved control and optimization of the process. This chapter provides a detailed review on the applicability and significance of PBMs in drug product manufacturing and is aimed to provide greater insight into the field of process systems engineering.

Process dynamics and control of API manufacturing and purification processes

Abstract The pharmaceutical industries have started transitioning toward continuous mode of manufacturing recently. Due to many advantages of the continuous manufacturing over the traditional alternatives, the industries are putting huge effort to efficiently adapt the continuous processing mode. However, even now, the drug product (tablet) manufacturing is separate from the drug substance (active ingredient) manufacturing and no direct connection exists between the two. The physical properties of the active pharmaceutical ingredient (API) crystals (e.g., crystal size, shape, etc.) affect the critical quality attributes (CQAs) of the final solid dosage forms (tablets). In this work a continuous integrated flowsheet model (mathematical representation for in silico simulation) has been developed, which integrates the API purification, separation with a downstream tablet manufacturing unit operation (powder mixing). This flowsheet can be used to study the effect of upstream API properties on the downstream product attributes. The flowsheet model consists of crystallization, filtration (API separation), drying (API purification) followed by a powder-blending operation (to obtain the final formulation). Each unit operation has been developed from first principles and connected in a continuous framework such that the output of one unit operation becomes the input of the next unit operation. These integrated unit operations are highly interactive along with the presence of process delays. A hybrid model predictive control-proportional integral derivative control system has been designed and presented for the continuous flowsheet model as well.