Averaging level control to reduce off-spec material in a continuous pharmaceutical pilot plant

The judicious use of buffering capacity is important in the development of future continuous pharmaceutical manufacturing processes. The potential benefits are investigated of using optimal-averaging level control for tanks that have buffering capacity for a section of a continuous pharmaceutical pilot plant involving two crystallizers, a combined filtration and washing stage and a buffer tank. A closed-loop dynamic model is utilized to represent the experimental operation, with the relevant model parameters and initial conditions estimated from experimental data that contained a significant disturbance and a change in setpoint of a concentration control loop. The performance of conventional proportional-integral (PI) level controllers is compared with optimal-averaging level controllers. The aim is to reduce the production of off-spec material in a tubular reactor by minimizing the variations in the outlet flow rate of its upstream buffer tank. The results show a distinct difference in behavior, with the optimal-averaging level controllers strongly outperforming the PI controllers. In general, the results stress the importance of dynamic process modeling for the design of future continuous pharmaceutical processes

Continuous Membrane-Assisted Crystallization To Increase the Attainable Product Quality of Pharmaceuticals and Design Space for Operation

Continuous manufacturing is an important paradigm shift in pharmaceutical industries and has renewed the interest in continuous crystallization. The combination of crystallization and membranes is a promising hybrid technology for separation and purification of pharmaceuticals. The impact of membranes as an extension to conventional continuous crystallization processes on attainable product quality and design space is investigated systematically using model-based optimization. The proposed model is based on a full population balance such that all relevant crystallization phenomena can be included and is solved using a first-order discretization scheme with a hybrid grid. A case study involving continuous crystallization of paracetamol using a series of mixed suspension, mixed product removal (MSMPR) crystallizers is presented to illustrate the approach. The results show that the attainable size and design space can be enlarged significantly by extending conventional crystallization with membranes. In particular, larger crystals or shorter residence times can be achieved. Furthermore, to obtain a crystal size within a desired range, a broader range of temperatures can be applied, which increases operational flexibility

A Plant-Wide Dynamic Model of a Continuous Pharmaceutical Process

The pharmaceutical industry has historically benefited from high profit margins for their products, and over the years limited efforts have been made to change the main manufacturing concept from batch into continuous. However, over the past decade, as a result of an increased demand for more efficient and cost-effective processes, interest has grown in the application of continuous manufacturing to address economical and technical issues in the pharmaceutical field. This option is becoming more viable, particularly with the implementation of new process analytical technology (PAT). In this paper, we present a plant-wide mathematical model inspired by a recently developed continuous pharmaceutical pilot plant. This model is first used to simulate a base case that shows typical limitations in achieving simultaneously high productivity and quality. The main critical quality attribute considered is the purity of the final product. To alleviate the base case limitations and improve the pilot plant performance, the effects of several design parameters are investigated and the most critical are identified. In addition, alternative start-up scenarios are considered to improve the transient performance of the pilot plant, particularly time to steady state. The environmental footprint of the pilot plant is evaluated and shown to be low

An Air-Lift Crystallizer Can Suppress Secondary Nucleation at a Higher Supersaturation Compared to a Stirred Crystallizer

Secondary nucleation is suppressed in an air-lift crystallizer at levels of supersaturation where in a stirred crystallizer a clear contribution of secondary nucleation is visible. A comparison of batch crystallization of l-ascorbic acid in an air-lift crystallizer and in a stirred crystallizer is presented. The results demonstrate that at low supersaturation, secondary nucleation can be suppressed in both the air-lift crystallizer and the stirred crystallizer. At higher supersaturation, nucleation starts to dominate in the air-lift crystallizer. At an intermediate level of supersaturation, a clear contribution of secondary nucleation in the final product obtained from the stirred crystallizer is visible. However, experiments with similar conditions in the air-lift crystallizer show a significantly smaller contribution of secondary nucleation. The observed enlargement of the operating window in terms of supersaturation where secondary nucleation is suppressed in an air-lift crystallizer may have important practical consequences. Air-lift crystallizers can potentially operate with a higher crystal growth rate and the operating window for design and automated control can be extended

Minimization of Attrition and Breakage in an Airlift Crystallizer

Minimization of secondary nucleation by attrition in industrial crystallizers is a major challenge. In this work, a novel airlift crystallizer has been designed, constructed, and experimentally tested aiming at the reduction of attrition by using air for mixing instead of a stirrer or a circulation pump. It is experimentally demonstrated that in this crystallizer ideal growth, i.e., growth of crystals without any nucleation, can be approached up to a seeding load of 0.5% and crystal size of up to 600 μm. Attrition is considerably decreased in an airlift crystallizer compared to conventional impeller-mixed crystallizers. This air-mixed crystallizer enables the production of crystals of high quality and offers a large flexibility of the final crystal size by manipulating the air flow rate and the sparger design. Comparison of different designs showed a large effect of a gas disengagement zone on the performance of the crystallizer, especially when large crystals were desired. The disengagement zone allows high circulation velocities and thus good mixing without entrainment of the gas bubbles in the downcomer, approaching a uniform suspension of the crystals

The application of a plant-wide control strategy for an integrated continuous pharmaceutical pilot plant.

Continuous manufacturing offers potential opportunities for the improved manufacturing of pharmaceutical products. A key challenge is the development of an appropriate control strategy. The experimental application of an automated control strategy is presented for an end-to-end continuous pharmaceutical pilot plant. The process starts from an advanced intermediate compound and finishes with the tablet formation steps. The focus of the experimental results is on the design and performance of the control loops needed to produce a slurry of an active pharmaceutical ingredient and a solvent with specified material properties. The results demonstrate that automated control can successfully keep critical material attributes close to the desired set points for a sustained period of operation. This work aims to contribute to the development of future continuous pharmaceutical processes by providing a realistic case study of automated control of an integrated, continuous, pharmaceutical pilot plant

Development of a multi-step synthesis and workup sequence for an integrated, continuous manufacturing process of a pharmaceutical

The development and operation of the synthesis and workup steps of a fully integrated, continuous manufacturing plant for synthesizing aliskiren, a small molecule pharmaceutical, are presented. The plant started with advanced intermediates, two synthetic steps away from the final active pharmaceutical ingredient, and ended with finished tablets. The entire process was run on several occasions, with the data presented herein corresponding to a 240 h run at a nominal throughput of 41 g h-1 of aliskiren. The first reaction was performed solvent-free in a molten condition at a high temperature, achieving high yields (90%) and avoiding solid handling and a long residence time (due to higher concentrations compared to dilute conditions when run at lower temperatures in a solvent). The resulting stream was worked-up inline using liquid-liquid extraction with membrane-based separators that were scaled-up from microfluidic designs. The second reaction involved a Boc deprotection, using aqueous HCl that was rapidly quenched with aqueous NaOH using an inline pH measurement to control NaOH addition. The reaction maintained high yields (90-95%) under closed-loop control despite process disturbances. © 2014 American Chemical Society

Development of a Multi-Step Synthesis and Workup Sequence for an Integrated, Continuous Manufacturing Process of a Pharmaceutical

The development and operation of the synthesis and workup steps of a fully integrated, continuous manufacturing plant for synthesizing aliskiren, a small molecule pharmaceutical, are presented. The plant started with advanced intermediates, two synthetic steps away from the final active pharmaceutical ingredient, and ended with finished tablets. The entire process was run on several occasions, with the data presented herein corresponding to a 240 h run at a nominal throughput of 41 g h^–1 of aliskiren. The first reaction was performed solvent-free in a molten condition at a high temperature, achieving high yields (90%) and avoiding solid handling and a long residence time (due to higher concentrations compared to dilute conditions when run at lower temperatures in a solvent). The resulting stream was worked-up inline using liquid–liquid extraction with membrane-based separators that were scaled-up from microfluidic designs. The second reaction involved a Boc deprotection, using aqueous HCl that was rapidly quenched with aqueous NaOH using an inline pH measurement to control NaOH addition. The reaction maintained high yields (90–95%) under closed-loop control despite process disturbances