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Application of Process Systems Engineering in Continuous Pharmaceutical and Biopharmaceutical...
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Application of Process Systems Engineering in Continuous Pharmaceutical and Biopharmaceutical Manufacturing

A special issue of Processes (ISSN 2227-9717). This special issue belongs to the section "Pharmaceutical Processes".

Deadline for manuscript submissions: 10 April 2025 | Viewed by 9346

Special Issue Editor

Dr. Ravendra Singh

E-Mail Website
Guest Editor
Faculty of Chemical and Biochemical Engineering, Rutgers University, Piscataway, NJ 08854, USA
Interests: Process Systems Engineering (PSE); advanced process control; process modeling and simulation; process monitoring; PAT; QbD; system identification; pharmaceutical manufacturing
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Currently, pharmaceutical industries are undergoing a paradigm shift from traditional batch to novel continuous manufacturing. Few pharmaceutical products have been recently approved by the US Food and Drug Administration (FDA) for continuous production, and several others are under evaluation. Pharmaceutical industries and regulators (e.g., FDA) are strongly promoting smarter continuous manufacturing (CM). There are several advantages but also different scientific challenges regarding this paradigm shift. Efficient and optimum process design, process automation, real-time monitoring and control, material traceability, the diversion of non-confirming products, and real-time release are among the advantages of CM that are scientifically challenging to address. Systematic process system engineering (PSE) methods and tools are, therefore, needed to efficiently overcome the obstacles on the path of CM shift and to develop smarter continuous pharmaceutical manufacturing processes.

This Special Issue on “Application of Process Systems Engineering in Continuous Pharmaceutical and Biopharmaceutical Manufacturing” aims to collect high-quality research studies addressing challenges in adapting the continuous pharmaceutical manufacturing process. The submission of manuscripts demonstrating the importance of system engineering to further modernize the continuous pharmaceutical manufacturing process is highly encouraged. Manuscripts related to both finished solid-dose products (tablets and capsules) and substances (API) will be considered for publication. Topics include, but are not limited to, the following:

  • Design and operation of the continuous pharmaceutical manufacturing process;
  • Dynamic modeling and simulation of continuous and/or batch pharmaceutical manufacturing processes;
  • Optimization of the continuous pharmaceutical manufacturing process;
  • Control of the continuous pharmaceutical manufacturing process;
  • Process analytical technology (PAT);
  • Quality by Design (QbD);
  • Data science of the continuous pharmaceutical manufacturing process;
  • Material characterization and pharmaceutical databases.

Dr. Ravendra Singh
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Processes is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2400 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • continuous pharmaceutical manufacturing
  • dynamic modeling and simulation
  • process control
  • process analytical technology (PAT)
  • Quality by Design (QbD)
  • material attributes
  • process and plant design
  • data science
  • tablets
  • API

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Further information on MDPI's Special Issue polices can be found here.

Published Papers (5 papers)

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Research

15 pages, 2998 KiB  
Article
Developing Lead Compounds of eEF2K Inhibitors Using Ligand–Receptor Complex Structures
by Jiangcheng Xu, Wenbo Yu, Yanlin Luo, Tiantao Liu and An Su
Processes 2024, 12(7), 1540; https://doi.org/10.3390/pr12071540 - 22 Jul 2024
Viewed by 1022
Abstract
The eEF2K, a member of the α-kinase family, plays a crucial role in cellular differentiation and the stability of the nervous system. The development of eEF2K inhibitors has proven to be significantly important in the treatment of diseases such as cancer and Alzheimer’s. [...] Read more.
The eEF2K, a member of the α-kinase family, plays a crucial role in cellular differentiation and the stability of the nervous system. The development of eEF2K inhibitors has proven to be significantly important in the treatment of diseases such as cancer and Alzheimer’s. With the advancement of big data in pharmaceuticals and the evolution of molecular generation technologies, leveraging artificial intelligence to expedite research on eEF2K inhibitors shows great potential. Based on the recently published structure of eEF2K and known inhibitor molecular structures, a generative model was used to create 1094 candidate inhibitor molecules. Analysis indicates that the model-generated molecules can comprehend the principles of molecular docking. Moreover, some of these molecules can modify the original molecular frameworks. A molecular screening strategy was devised, leading to the identification of five promising eEF2K inhibitor lead compounds. These five compound molecules demonstrated excellent thermodynamic performance when docked with eEF2K, with Vina scores of −12.12, −16.67, −15.07, −15.99, and −10.55 kcal/mol, respectively, showing a 24.27% improvement over known active inhibitor molecules. Additionally, they exhibited favorable drug-likeness. This study used deep generative models to develop eEF2K inhibitors, enabling the treatment of cancer and neurological disorders. Full article
(This article belongs to the Special Issue Application of Process Systems Engineering in Continuous Pharmaceutical and Biopharmaceutical Manufacturing)
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17 pages, 4847 KiB  
Article
Inverse Method-Based Kinetic Modelling and Process Optimization of Reverse-Phase Chromatography for Molnupiravir Synthesis
by Athanasios Kritikos, Ravendra Singh, Fernando Muzzio and George Tsilomelekis
Processes 2024, 12(6), 1273; https://doi.org/10.3390/pr12061273 - 20 Jun 2024
Viewed by 1067
Abstract
Our research addresses the shift towards continuous manufacturing in the pharmaceutical industry, focusing on optimizing chromatographic separation for the synthesis of molnupiravir. Using an inverse method with six different inlet concentrations for a single objective function, we systematically evaluated the adsorption of key [...] Read more.
Our research addresses the shift towards continuous manufacturing in the pharmaceutical industry, focusing on optimizing chromatographic separation for the synthesis of molnupiravir. Using an inverse method with six different inlet concentrations for a single objective function, we systematically evaluated the adsorption of key intermediates, i.e., hydroxylamine and isobutyrate, in an isocratic solvent, determining the relevant isotherm constants. The study systematically evaluates the effects of operational variables, including flowrate, column geometry, dispersivity coefficient, and injection volume, on chromatographic performance. Findings reveal that specific operational adjustments, such as reducing flowrates or altering column dimensions, significantly influence retention times and peak profiles, thus potentially impacting the efficiency of molnupiravir production. Utilizing the inverse method, we efficiently determined equilibrium isotherms by integrating a nonlinear chromatography model and adjusting isotherm parameters to match the observed band profiles. Our research offers critical insights into optimizing chromatographic separation performance through precise operational control, leveraging computational tools for rapid and adaptable drug development. Full article
(This article belongs to the Special Issue Application of Process Systems Engineering in Continuous Pharmaceutical and Biopharmaceutical Manufacturing)
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23 pages, 11195 KiB  
Article
Technoeconomic Analysis of Intensified PEGylated Biopharmaceutical Recombinant Protein Production: Alpha Antitrypsin as a Model Case
by Salem Alkanaimsh, Abdullah M. Alsalal and Hesham El-Touney
Processes 2024, 12(5), 979; https://doi.org/10.3390/pr12050979 - 10 May 2024
Viewed by 1659
Abstract
Alpha-1 antitrypsin deficiency (AATD) is a genetic disorder characterized by the insufficient production of the AAT protein. Due to availability limitations, not all AATD patients receive protein therapy treatment. In this study, the technoeconomic analysis of different processes (conventional and intensified) producing 200 [...] Read more.
Alpha-1 antitrypsin deficiency (AATD) is a genetic disorder characterized by the insufficient production of the AAT protein. Due to availability limitations, not all AATD patients receive protein therapy treatment. In this study, the technoeconomic analysis of different processes (conventional and intensified) producing 200 kg/year of PEGylated recombinant AAT (PEG-AAT) using a Chinese hamster ovary cell line was investigated. All bioprocesses consist of upstream, downstream, and PEGylation sections. A base-case model (process A) of the conventional fed-batch production bioreactor was developed using SuperPro Designer software (Version 13) to evaluate the economic feasibility of the process. The cost of goods (COG) was estimated to be approximately USD 387.6/g. Furthermore, an intensified process (B) was modeled and evaluated to reduce the COG. Process intensification was implemented in the process (N-1 perfusion bioreactor). The specific operating COG for process B was found to be 10% less than that of process A. Scenario analysis was performed to assess the impact of process capacity (100–1000 kg/year) and cell-specific productivity (30–90 pg/cell/day). With an increase in process capacity, the specific operating COG was reduced for all processes. Increasing cell-specific productivity decreases the specific operating COG at different rates for each process, depending on the titer level. Future investigations into the PEGylation section are required since it has the highest COG of all the sections. Full article
(This article belongs to the Special Issue Application of Process Systems Engineering in Continuous Pharmaceutical and Biopharmaceutical Manufacturing)
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15 pages, 5612 KiB  
Article
Kinetic Investigation of the Oxidative Thermal Decomposition of Levonorgestrel
by Amalia Ridichie, Adriana Ledeţi, Francisc Peter, Ionuţ Ledeţi, Cornelia Muntean and Matilda Rădulescu
Processes 2023, 11(11), 3210; https://doi.org/10.3390/pr11113210 - 10 Nov 2023
Viewed by 1270
Abstract
In this study, we have focused on studying the heterogenous degradation kinetics regarding the decomposition of the emergency contraceptive agent levonorgestrel (LNG), which is a second-generation synthetic progestogen that is the active component of the racemic mixture of norgestrel. The degradation processes of [...] Read more.
In this study, we have focused on studying the heterogenous degradation kinetics regarding the decomposition of the emergency contraceptive agent levonorgestrel (LNG), which is a second-generation synthetic progestogen that is the active component of the racemic mixture of norgestrel. The degradation processes of the active pharmaceutical ingredient (API) were compared with the ones obtained from a model system containing the API along with the excipients that are found in a commercialized pharmaceutical formulation in a mass ratio of 1:1 (LNGMIX), in order to observe if the excipients have a stabilizing or destabilizing effect on the degradation of this progestogen. To achieve this, the following investigational methods were used: FTIR (Fourier transform infrared) spectroscopy and thermal analysis (TG/DTG/DSC analysis). For the kinetic analysis, the data obtained from two main decomposition processes observed on the DTG curves were used and processed with a preliminary method, namely ASTM E698, and two isoconversional methods: Friedman and Flynn–Wall–Ozawa. The isoconversional study revealed that the decomposition mechanisms of both LNG and LNGMIX are complex, and the excipients have a stabilizing effect on the decomposition of the API in tablet. Full article
(This article belongs to the Special Issue Application of Process Systems Engineering in Continuous Pharmaceutical and Biopharmaceutical Manufacturing)
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12 pages, 5814 KiB  
Article
Measuring the Flow Functions of Pharmaceutical Powders Using the Brookfield Powder Flow Tester and Freeman FT4
by Mark Christopher Leaper
Processes 2021, 9(11), 2032; https://doi.org/10.3390/pr9112032 - 13 Nov 2021
Cited by 5 | Viewed by 3105
Abstract
This study examined the feasibility of combining data from different powder flow testers to determine the flow function characteristics of pharmaceutical powders. The Brookfield PFT and Freeman FT4 can measure flow function over different scales of consolidation load but were found to be [...] Read more.
This study examined the feasibility of combining data from different powder flow testers to determine the flow function characteristics of pharmaceutical powders. The Brookfield PFT and Freeman FT4 can measure flow function over different scales of consolidation load but were found to be most complementary with CRM limestone powder and lactose. The brittle behaviour of Easytab particles at higher loads made obtaining repeatable results with the FT4 challenging. By using the method of Wang et al., where the flow function coefficient ffc is plotted against the dimensionless cohesion C* (measured cohesion Ta divided by the initial compaction I), a plot was formed which could be used to predict the behaviour of other systems, which compared well with previous studies. Full article
(This article belongs to the Special Issue Application of Process Systems Engineering in Continuous Pharmaceutical and Biopharmaceutical Manufacturing)
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