Continuous Manufacturing Processes

In this paper, we present the development of a safe water-based synthesis of 1,2,3-triazole using cheap raw materials. Starting from glyoxal and hydrazine, a safe and efficient three-step end-to-end continuous process was developed. This protocol transforms heterogeneous batch reactions into a homogeneous streamlined continuous flow system. This advancement not only obviated the separation of hazardous intermediates, thereby mitigating potential risks, but also significantly diminished the reaction time of each step. This has ensured a rapid and stable supply of 1,2,3-triazole for downstream product development such as tazobactam. Additionally, the study delves into the insights gained from transitioning from batch reactions to continuous flow processes, highlighting the practical and safety benefits of continuous flow synthesis.

A novel manufacturing strategy based on continuous processing, integrated with online/inline monitoring tools, coupled with an advanced automatic feedback control system is highly desired for efficient Quality by Design (QbD)-based manufacturing of the next generation of pharmaceutical products with optimal consumption of time, space and resources. In this work, an advanced hybrid MPC-PID control system as well as a simpler PID controller for a direct compaction continuous tablet manufacturing process has been designed and implemented for a pilot-scale pharmaceutical process. An NIR sensor, an online NIR prediction tool, a PAT data management tool, an OPC communication protocol, a standard control platform and control hardware have been used to close the control loop. A systematic methodology to design and implement the control system has been also proposed. A control framework with features such as the option to run the plant in open-loop as well as in a closed-loop scenario has been developed. Furthermore, within the closed-loop scenario, options for a simpler PID, a dead time compensator (Smith predictor) as well as an advanced model predictive controller have been included. The feature to run the control strategy in simulation mode has been added to the control platform to facilitate virtual control system design and performance evaluation. Two case studies involving a direct compaction continuous tablet manufacturing process have been considered to demonstrate the closed-loop operation. Case Study 1 was completed at Rutgers University and constituted the use of a continuous cylindrical blender with a rotating screw. Case Study 2 was based on a continuous tumble mixer and was completed at the University of Puerto Rico—Mayaguez Campus (UPRM).

Walnut is one of the high yielding fruit crops grown in union territory of Jammu and Kashmir (J&K) in India. However, processing of walnuts in J&K is being carried out manually, which is very tedious, troublesome, and time and labor consuming. Thus, the present work was undertaken with an aim to develop a single mechanized continuous system for post‐harvest handling and processing of walnuts. The innovation composed of dehulling, bleaching, washing, drying, and grading units, besides conveyors to carry walnuts from one unit to another. The dehulling efficiency (95.70%), bleaching efficiency (96.28%), washing efficiency (99.10%), and grading efficiency (97.43%) recorded for the developed system are much higher than the manual processing. Furthermore, number of partially dehulled, un‐dehulled, partially bleached, unbleached, and damaged walnut percentages were recorded significantly (p < 0.05) lower whereas fully dehulled and fully bleached walnut percentages were recorded significantly (p < 0.05) higher in case of developed system as compared with manual processing. Overall capacity and efficiency of the developed system were recorded as 800 kg/day and 97.02%, respectively. The labor requirement for processing 1 ton of walnuts using developed system was determined to be 10 man h. The economic analysis indicated that adoption of developed system for walnut processing can be highly beneficial and economic. Thus, developed system can be a feasible alternative to minimize the post‐harvest losses, to maintain the quality, and to overcome the drudgery, boredom, and constraints associated with manual post‐harvest handling and processing of walnuts.Practical ApplicationsJammu and Kashmir (J&K) has the largest share in India's total walnut production. However, from the last few years, there has been a setback to the export trade potential of walnuts in India, mainly due to import of walnuts from China and California. The walnuts from California and China have better consumer acceptability than walnuts of J&K, which has badly affected the walnut trade in India. In J&K, post‐harvest handling of walnuts is being done manually without any scientific and mechanical arbitration, which leads to quality deterioration of walnuts. Therefore, in order to compete at international level, there is an immediate need to shift the post‐harvest handling of walnuts from manual to mechanized. Thus, the adoption of developed continuous inshelled walnut processing system can play a vital role in sustaining the rural economy of J&K through production and sale of good quality walnuts. Furthermore, the developed system can serve as a benchmark for establishment of modern walnut processing units, which can lead to employment generation and boost the walnut trade in J&K.

This paper presents the design and experimental verification of a continuous processing system for the production of microcellular polymer sheets based on the axiomatic design approach. In this work, the axiomatic design principles are effectively utilized as a structured framework from which to formulate an innovative microcellular sheet extrusion system. The design principles serve as essential guidelines in approaching the problem, synthesizing a solution, determining critical process parameters, and evaluating system performance. Microcellular polymers are an innovative cellular polymer technology characterized by cell sizes on the order of 0.1 to 10 microns and cell densities on the order of 109 to 1015 cells per cubic centimeter. Due to their extreme cell densities and minute cell size, these materials require advanced process technologies which surpass the capabilities of conventional foam processes. The microcellular-sheet processing system design is based on three sub-processes which include the processing of the polymer matrix, the processing of the microcellular structure, and the processing of the net shape. The creation of a microcellular structure is achieved by dissolving large gas concentrations into a polymer matrix and subjecting the saturated system to a rapid thermodynamic state change. This creates an unstable supersaturated-matrix which drives the nucleation of billions of microcells. Stable cells then grow as gas diffuses into the cells, reducing the bulk density of the material. Based on these fundamental processing requirements, a hierarchical design strategy is used to synthesize the overall production system such that each of the processing functions is independently satisfied by a unique design parameter or process variable.

Over the last several years, continuous manufacturing of pharmaceuticals has evolved from bulk APIs and solid oral dosages into the more complex realm of biologics. The development of continuous downstream processing techniques has allowed biologics manufacturing to realize the benefits (e.g., improved economics, more consistent quality) that come with continuous processing. If relevant processing techniques and principles are selected, the opportunity arises to develop continuous manufacturing designs for additional pharmaceutical products including liposomal drug formulations. Liposome manufacturing has some inherent aspects that make it favorable for a continuous process. Other aspects such as formulation refinement, materials of construction, and aseptic processing need development, but present an achievable challenge. This paper reviews the current state of continuous manufacturing technology applicable to liposomal drug product manufacturing and an assessment of the challenges and potential of this application.

A novel strategy has been established, in the laboratory scale, for the generation of the popular thermosetting resin phenol formaldehyde (PF; resole), through a continuous process using a tubular reactor, which is usually developed in the commercial scale through a batch process. A refractive index technique is employed to evaluate the optimum residence time within the tubular reactor to obtain a commercial grade equivalent of PF resin. The unreacted free formaldehyde level has been found to be very low in the resole resin prepared by using the new route. The initial characterization of the resin has been done through Fourier transform infrared spectroscopy and gel permeation chromatography. The cure characteristics of the resin have been analyzed through differential scanning calorimetry. The degradation features of the cured resole are investigated using a thermo gravimetric analyzer and the fractured surfaces are analyzed through scanning electron microscopy. It has been confirmed that the adverse effects of a batch reactor process can be significantly reduced by adopting a continuous resin manufacturing process for PF resin which can be successfully extended to commercialization after optimization.

High-yield production of enantiopure 2-hydroxy-2-(2′-chlorophenyl) acetic acid by long-term operation of a continuous packed bed reactor

Challenges in tracing material flow passing a loss-in-weight feeder in continuous manufacturing processes

Development of a high-fidelity digital twin using the discrete element method for a continuous direct compression process. Part 1. Calibration workflow

Continuous treatment process of mercury removal from aqueous solution by growing recombinant E. coli cells and modeling study

Affordability of biopharmaceuticals continues to be a challenge, particularly in developing economies. This has fuelled advancements in manufacturing that can offer higher productivity and better economics without sacrificing product quality in the form of an integrated continuous manufacturing platform. While platform processes for monoclonal antibodies have existed for more than a decade, development of an integrated continuous manufacturing process for bacterial proteins has received relatively scant attention. In this study, we propose an end-to-end integrated continuous downstream process (from inclusion bodies to unformulated drug substance) for a therapeutic protein expressed in Escherichia coli as inclusion body. The final process consisted of a continuous refolding in a coiled flow inverter reactor directly coupled to a three-column periodic counter-current chromatography for capture of the product followed by a three-column con-current chromatography for polishing. The continuous bioprocessing train was run uninterrupted for 26 h to demonstrate its capability and the resulting output was analyzed for the various critical quality attributes, namely product purity (>99%), high molecular weight impurities (<0.5%), host cell proteins (<100 ppm), and host cell DNA (<10 ppb). All attributes were found to be consistent over the period of operation. The developed assembly offers smaller facility footprint, higher productivity, fewer hold steps, and significantly higher equipment and resin utilization. The complexities of process integration in the context of continuous processing have been highlighted. We hope that the study presented here will promote development of highly efficient, universal, end-to-end, fully continuous platforms for manufacturing of biotherapeutics. © 2016 American Institute of Chemical Engineers Biotechnol. Prog., 33:998-1009, 2017.

The capital, operating, and overall costs of a dedicated continuous manufacturing process to synthesize an active pharmaceutical ingredient (API) and formulate it into tablets are estimated for a production scale of 2000 t of tablets per year, with raw material cost, production yield, and API loading varied over broad ranges. Costs are compared to batch production in a dedicated facility. Synthesis begins with a key organic intermediate three synthetic steps before the final API; results are given for key intermediate (KI) costs of $100 to $3000/kg, with drug loadings in the tablet of 10 and 50 wt %. The novel continuous process described here is being developed by an interdisciplinary team of 20 researchers. Since yields are not yet well-known, and continuous processes typically have better yields than batch ones, the overall yields of the continuous processes with recycling were set equal to that of the batch process. Without recycling, yields are 10% lower, but less equipment is required. The continuou...

In this paper, we focus our studies on a distributed keyword continuous query processing system that is built on distributed hash tables. Treating bandwidth as a first-class resource, we propose novel query indexing algorithms including MHI and SAP-MHI, multicast-based document announcement, and adaptive query resolution to reduce bandwidth cost. Our detailed simulations show that our proposed techniques, combined together, effectively and greatly cut down bandwidth consumption.

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.

An automated continuous flow system capable of producing protected deoxy‐sugar donors from commercial material is described. Four 2,6‐dideoxy and two 3‐amino‐2,3,6‐trideoxy sugars with orthogonal protecting groups were synthesized in 11–32 % overall yields in 74–131.5 minutes of total reaction time. Several of the reactions were able to be concatenated into a continuous process, avoiding the need for chromatographic purification of intermediates. The modular nature of the experimental setup allowed for reaction streams to be split into different lines for the parallel synthesis of multiple donors. Further, the continuous flow processes were fully automated and described through the design of an open‐source Python‐controlled automation platform.