Zoltan K Nagy

Loughborough University | Lough · Department of Chemical Engineering

Raman spectroscopy is one of the important process analytical technology tools available for implementation in the continuous manufacturing of oral solid dosages. The aim of this study was to investigate several practical considerations in generating real-time measurements using Raman spectrometer at a tablet press feed frame, including the effects...

Current technologies to measure granule flowability involve at-line methods that can take hours to perform. This is problematic for a continuous dry granulation tableting line, where the quality assurance and control of the final tablet products depend on real-time monitoring and control of powder flowability. Hence, a real-time alternative is need...

The pharmaceutical manufacturing sector needs to rapidly evolve to absorb the next wave of disruptive industrial innovations – Industry 4.0. This involves incorporating technologies like artificial intelligence and 3D printing to automate and personalize the drug production processes. This study aims to build a formulation and process design (FPD)...

Encapsulation of paracetamol (PCM) onto poly(ɛ-caprolactone) (PCL) polymer matrix by anti-solvent displacement method was investigated using a glass capillary microfluidics. Five (5) independent parameters involved PCL concentration (A), microfluidics orifice size (B), flow rate ratios (C), surfactant concentration (D) and paracetamol percentage lo...

This study details the development of simulation-aided design, development, and successful operation of a continuous liquid-liquid extraction platform made with 1.5 mm tubing for the extraction of 2-chloroethyl isocyanate, an important reagent in the synthesis of cancer drugs. Preliminary solvent screening was carried out with partition coefficient...

Continuous manufacturing and closed‐loop quality control are emerging technologies that are pivotal for next‐generation pharmaceutical modernization. We develop a process control framework for a continuous carousel for integrated filtration‐drying of crystallization slurries. The proposed control system includes model‐based monitoring and control r...

In this paper, continuous crystallization of Atorvastatin calcium (ASC) using a continuous oscillatory baffled crystallizer (COBC) has been investigated. Like most API manufacturing, ASC is manufactured batchwise and the pure API is recovered via batch combined cooling and antisolvent crystallization (CCAC) process, which has the challenges of low...

Over the past two decades, pharmaceutical manufacturing has seen significant modernization due to the digitalization of manufacturing as more manufacturers adopt Industry 4.0 standards. The FDA launched the quality-by-design and quality-by-control initiatives as steps to ensure this digitalization in pharmaceutical manufacturing may proceed alongsi...

This article introduces ContCarSim, a benchmark simulator for the development and testing of quality-by-design and quality-by-control strategies in the continuous intensified filtration-drying of paracetamol/ethanol slurries on a novel carousel technology, developed by Alconbury Weston Ltd (United Kingdom). The simulator is based on a detailed mech...

The development of a process model for the batch cooling crystallization of an anticancer drug from Takeda Pharmaceuticals is presented. The compound forms needle-like crystals that exhibit significant variation in shape (aspect ratio) during the crystallization. The parameters of a two-dimensional population balance model were fit using experiment...

Active pharmaceutical ingredient (API) separation from synthesis and crystallization mother liquors is typically carried out in pharmaceutical manufacturing through filtration and drying. These steps are of utmost importance, as impurities herein retained will inevitably end up in the drug product. Recently, a novel carousel has been developed for...

The pharmaceutical industry has seen more interest in shifting from traditional fully batch operation to continuous manufacturing. With these shifts in mind and the adoption of industry 4.0 standards, digital tools are required to ensure critical medicines can be manufactured with quality guarantees. PharmaPy is one such tool that can create a digi...

The development of condition monitoring systems often follows a modular scheme where some systems are already embedded in certain equipment by their manufacturers, and some are distributed across various equipment and instruments. This work introduces a framework for guiding the modular development of monitoring systems and integrating them into a...

Active control strategies play a vital role in modern pharmaceutical manufacturing. Automation and digitalization are revolutionizing the pharmaceutical industry and are particularly important in the shift from batch operations to continuous operation. Active control strategies provide real-time corrective actions when departures from quality targe...

Controllers are often tuned during plant commissioning, with a fixed process model. However, over time degradation can occur in the process, the process model and the controller, making it necessary to either re-tune the controller or re-identify the process model. Authors have proposed a variety of approaches to identify plant-model mismatch (PMM)...

We report progress of an ongoing work to develop a virtual sensor for flowability, which is a critical tool for enabling real time process monitoring in a granulation line. The sensor is based on camera imaging to measure the size and shape distribution of granules produced by wet granulation. Then, statistical methods were used to correlate them w...

The continuous crystallization approach provides the opportunity to intensify production and improve the quality of crystals manufacturing. This study examined the effect of impurities on lactose crystallization in the continuous mixed suspension mixed product removal (MSMPR) crystallizer. Two impurities usually present in acid whey, protein and la...

The transition from batch to continuous processes in the pharmaceutical industry has been driven by the potential improvement in process controllability, product quality homogeneity, and reduction of material inventory. A quality-by-control (QbC) approach has been implemented in a variety of pharmaceutical product manufacturing modalities to increa...

Crystallinity in an amorphous solid dispersion (ASD) may negatively impact dissolution performance by causing lost solubility advantage and/or seeding crystal growth leading to desupersaturation. The goal of the study was to evaluate underlying dissolution and crystallization mechanisms resulting from residual crystallinity contained within bicalut...

While measurement and monitoring of powder/particulate mass flow rate are not essential to the execution of traditional batch pharmaceutical tablet manufacturing, in continuous operation, it is an important additional critical process parameter. It has a key role both in establishing that the process is in a state of control, and as a controlled va...

Process design and optimization continue to provide computational challenges as the chemical engineering and process optimization communities seek to address more complex and larger scale applications. Software tools for digital design and flowsheet simulation are readily available for traditional chemical processing applications such as in commodi...

This paper introduces a comprehensive mathematical model of a novel integrated filter-dryer carousel system, designed for continuously filtering, washing and drying a slurry stream into a crystals cake. The simulator includes models for dead-end filtration, cake washing and convective cake drying, based on dynamic multi-component mass, energy and m...

The integration of continuous unit operations imposes a challenge on the pharmaceutical companies aspiring to achieve plant-wide continuous manufacturing due to the additional complexity of the dynamic interactions, process control and quality assurance. To overcome this challenge, flowsheet modeling emerged as a viable tool to gain deeper process...

Small sample size (SSS) problems pose a tremendous challenge in modeling tasks due to insufficient training samples, especially in process industry where thousands of useless samples overwhelm very limited valuable samples, leading to deterioration on the prediction ability of trained models for key variables. In this study, the prediction ability...

Spherical agglomeration (SA) is a process intensification (PI) strategy, which can reduce the number of unit operations in pharmaceutical manufacturing. SA merges drug substance crystallization with drug product wet granulation, reducing capital and operating costs. However, SA is a highly nonlinear process, thus for its efficient operation model-b...

Flowsheet design and optimization constitute one of the key challenges in the chemical engineering and process optimization communities. Software tools for digital design and flowsheet simulation are readily available for traditional chemical processing problems such as distillation and hydrocarbon processing, however tools for pharmaceutical manuf...

In the last decade, pharmaceutical manufacturing has been undergoing a modernization trend, promoted by the US Food and Drug Administration (FDA) with the Quality-by-Design (QbD) initiative. However, in most of the cases, the product quality is still controlled in open-loop, and pharmaceutical operation is carried out in the traditional batch mode,...

This work demonstrates a systematic development of a digital twin of a commercial active pharmaceutical ingredient (API) - Compound A - crystallization processes to be used for in-silico design of experiments (DoE) and process optimization. Eleven highly corelated kinetic parameters were estimated by exploiting an optimization approach with an evol...

Within the recent modernization of pharmaceutical manufacturing, an important milestone consists in developing enabling technologies for end-to-end continuous production of drug products. Continuous filtration, washing and drying of active pharmaceutical ingredients from mother liquors in upstream manufacturing are critical steps for achieving end-...

This paper presents the first-ever industrial application of the digital design of a complex, large-scale industrial continuous crystallization network. The aim of the work is to optimize a large-scale continuous crystallization network used for the purification of dextrose monohydrate, by introducing a novel robust model-based digital design frame...

Highly homogeneous low-dose (50 µg) tablets were produced incorporating perfectly free-flowing granules prepared by a fully integrated Continuous Manufacturing (CM) line. The adopted CM equipment consisted of a Twin-Screw Wet Granulator (TSWG), a Continuous Fluid Bed Dryer (CFBD) and a Continuous Sieving (CS) unit. Throughout the experiments a pre-...

As continuous manufacturing is evolving in the pharmaceutical industry, continuous filtration has emerged as a bottleneck for connecting the crystallization of the active pharmaceutical ingredient with the formulation of the final drug product. This work aims the modeling of filtration to improve the understanding of the process, to support the dev...

Real-time optimization (RTO) in cascade model predictive control (MPC) is a classic two-layer architecture for economic optimization and dynamic control. The two-layer architecture is always integrated with steady-state target calculation (SSTC) to guarantee the feasibility of the control target. In this paper, we present a modified SSTC algorithm...

In this work, a rapid direct design approach for crystallization processes was implemented using the novel Quality-by-Control (QbC) framework by sequentially applying antisolvent based supersaturation control (AS-SSC) and temperature driven direct nucleation control (T-DNC) strategies. This novel strategy was used to optimize and scale-up the batch...

This study describes an automated system used for high throughput screening of reaction conditions based on accelerated reactions occurring in small volumes of reagents. Reaction mixtures are prepared in array format using a fluid handling robot and spotted on a flat polytetrafluoroethylene plate at densities up to 6,144/plate. The reaction and ana...

Continuous manufacturing, an emerging technology in the pharmaceutical industry, has the potential to increase the efficiency, and agility of pharmaceutical manufacturing processes. To realize these potential benefits of continuous operations, effectively managing materials, equipment, analyzers, and data is vital. Developments for continuous pharm...

Compartment models (CMs) are widely used to capture typical hydrodynamic features of systems, generally having low computational cost. The main building blocks of the CMs are the continuous stirred tank reactor and plug flow reactor models. In this study, the hydrodynamics of two laboratory scale continuously oscillated baffled crystallizer systems...

Using process modeling to understand process dynamics and potentially explore the design space of a crystallization process is difficult because of its complex nature with many factors at play, such as initial concentration, supersaturation, seeding strategy, and flow pattern. In this work, a systematic approach is applied to sequentially estimate...

Pharmaceutical continuous manufacturing is essentially in a steady state, or in a state of control, in process operation, by which variations in critical material/product properties and process parameters can be monitored and controlled in real time within an acceptable range that enables the comprehensive implementation of the Quality by Design (Q...

Pharmaceutical continuous manufacturing has steadily progressed from the proof of concept to the pilot and industrial production in the past two decades, some of which have recently been approved by the US Food and Drug Administration (FDA), resulting in a greater demand on experience in process design and operation in pharmaceutical continuous man...

Crystallization is an economical separation and purification unit operation commonly used in the pharmaceutical industry as the last drug substance manufacturing step to obtain crystalline form active pharmaceutical ingredient (API). The quality attributes of crystallization products such as purity, crystal size, crystal shape, and polymorphic form...

The crystallisation kinetics of individual triacylglycerols (TAGs) were studied during the isothermal fractionation of palm oil. On filtration, entrainment of liquid olein within the stearin cake was found to significantly affect measured solid stearin compositions. These could be corrected for entrainment using a mass balance based method along wi...

A novel feedback control strategy by semi-batch implementation for cooling crystallization is proposed, in which the supersaturation is controlled by manipulating the feed flow rate of the concentrated solution rather than using the temperature. Different supersaturation control (SSC) approaches have been simulated and compared in three cooling cry...

The design of pharmaceutical crystallization processes is a challenging engineering problem because of the specific and versatile quality requirements of the end-product, amplified by the tight regulatory standards. The current industrial standard for crystallization process design is based on the use of the Quality-by-Design (QbD) framework, which...

In this work, a scale-up strategy based on the principles of direct design and Quality-by-Control (QbC) was applied and investigated using direct nucleation control (DNC). Process analytical technologies (PATs) were implemented for process monitoring and control. Antisolvent crystallization of indomethacin (IMC) was performed in a ternary solvent a...

An end-to-end continuous pharmaceutical manufacturing process was developed for the production of conventional direct compressed tablets on a proof-of-concept level for the first time. The output reaction mixture of the flow synthesis of acetylsalicylic acid was crystallized continuously in a mixed suspension mixed product removal crystallizer. The...

This article introduces the application of a novel supersaturation control (SSC) approach for the crystallization of heat-sensitive materials. Traditional SSC implements parabolic temperature profile with slow initial cooling that maximizes growth over nucleation, however, which may also promote heat degradation. The proposed semibatch SSC fixes th...

Spherical crystallization (SC) is a novel process intensification strategy, which can substantially reduce the manufacturing cost for solid oral dosage forms. However, although the manufacturability of the product agglomerates could be controlled, control over the product bioavailability has remained elusive. The major bottleneck over the simultane...

Continuous protein crystallization is a cost-effective alternative to traditional chromatographic purification techniques. However, proteins characteristically have slow growth rates, requiring long crystallization times to generate particles large enough for efficient isolation. In this work, spherical crystallization using an emulsion solvent dif...

Expectations for product quality assurance along with addressing social and business objectives such as accelerated time to market, combating drug shortages by mitigating manufacturing losses and recalls, achieving reduced operating and capital costs, personalizing medications, and streamlined regulatory compliance have ushered a paradigm shift in...

Antisolvent crystallization of indomethacin (IMC) was investigated in this work by using an acetone-methanol (66.5-33.5 wt%) mixture as solvent and water as antisolvent. Selecting the binary mixture as the solvent led to an increased yield of the batch process as the solubility of IMC is higher in the mixed solvents. Adding methanol to the solvent...

Pharmaceutical manufacturing has been largely carried out in batch mode, which has disadvantages such as batch-to-batch variations and difficult scale-up. As a result, the pharmaceutical industry is going through the paradigm shift to continuous manufacturing. Many unit operations have been studied for continuous operation; however, the bottleneck...

Supersaturation control (SSC) is a simple yet effective technique to control, among of other properties, the purity, shape and polymorphic form of crystals during the crystallization process. However, for the enantiotropic polymorph systems it is difficult to efficiently operate the traditional batch SSC because of the intersecting solubility lines...

A dual backlit imaging technique has been developed for liquid and solid phase residence time distribution (RTD) measurements in a mesoscale (millilitre) continuous oscillatory flow crystalliser with smooth periodic constrictions (herein known as the SPC mesoscale crystalliser). The pixel-based technique enables reliable determination and direct co...

Encrustation is a risk factor that can cause product and process failure in continuous crystallization processes. Mitigation, prevention or control of encrustation have been extensively researched. Various risk mitigation strategies proposed in the literature, such as coating of crystallizer walls, use of additives to control encrustation kinetics,...

Many active pharmaceutical ingredients (APIs) undergo degradation at high temperature. Optimum cooling profiles from first principle models usually do not consider this degradation mechanism. Generally, for maximization of the rate of crystal growth, a slow cooling profile is preferred. This however keeps the API solution at elevated temperatures f...

Data provided by in situ sensors is always affected by some level of impreciseness as well as uncertainty in the measurements due to process operation disturbance or material property variance. In-process data precision and reliability should be considered when implementing active product quality control and real-time process decision making in pha...

The Quality-by-Design (QbD) guidance issued by the US Food and Drug Administration (FDA) has catalyzed the modernization of pharmaceutical manufacturing practices including the adoption of continuous manufacturing. Active process control was highlighted recently as a means to improve the QbD implementation. This advance has since been evolving into...

Advances in continuous manufacturing in the pharmaceutical industry necessitate reliable process monitoring systems that are capable of handling measurement errors inherent in all sensor technologies and detecting measurement outliers to ensure operational reliability. The purpose of this work was to demonstrate data reconciliation (DR) and gross e...

Crystallization, often as the final isolation and purification step in drug substance manufacturing, has substantial impact on downstream efficiency and final drug product quality. It is a critical but challenging step in developing end-to-end continuous manufacturing, which has been identified as an emerging technology in the pharmaceutical manufa...

Spherical crystallization is a particle size enlargement technique that can provide significant process and micromeritic benefits to the production of active pharmaceutical ingredients. To this point, mechanistic studies of spherical crystallization systems have not used process analytical technologies to assist in developing an understanding of th...

The pharmaceutical industry has been undergoing a paradigm shift towards continuous manufacturing, under which novel approaches to real-time product quality assurance have been investigated. A new perspective, entitled Quality-by-Control (QbC), has recently been proposed as an important extension and complementary approach to enable comprehensive Q...

In this work, a vacuum-driven intermittent transfer technique has been implemented to solve transfer line blockage issues and facilitate steady-state cooling crystallization studies of α-glycine in a single- and 2-stage MSMPR crystallizer. Experimental residence time distribution (RTD) analysis of the stirred tank MSMPR cascade is performed using a...

In this paper, we focus on generating the reference trajectory to improve the economic performance in transient processes for model predictive control (MPC). We convert the trajectory generation problem to the shortest path problem which is one common problem in graph theory. For this purpose we construct a graph, also called the state-input graph,...

The principal method of drug delivery is by oral solid doses, the production of which often necessitates multiple post-crystallization unit operations to ensure content uniformity and/or enhance bioavailability. As an alternative to conventional dose production methods, applications of additive manufacturing technologies based on solvent- or melt-b...

Purpose Reliable process monitoring in real-time remains a challenge for the pharmaceutical industry. Dealing with random and gross errors in the process measurements in a systematic way is a potential solution. In this paper, we present a process model-based framework, which for given sensor network and measurement uncertainties will predict the m...

p>Through molecular dynamics simulations, we report on a new development concerned with creating hitherto unknown polymorphs by influencing crystallization with a suitably constituted electric field. The methodology has the potential to add to crystallization technology whose exploration has been so far limited to the manipulation of temperature, s...