Abstract:Continuous manufacturing (CM) has the potential to provide pharmaceutical products with better quality, improved yield and with reduced cost and time. Moreover, ease of scale-up, small manufacturing footprint and on-line/in-line monitoring and control of the process are other merits for CM. Regulating authorities are supporting the adoption of CM by pharmaceutical manufacturers through issuing proper guidelines. However, implementation of this technology in pharmaceutical industry is encountered by a number of… Show more
“…The model drug was aliskiren hemifumarate, and the throughput of the process was 45 g/h, with a residence time of 47 h. Subsequently, the first commercial-setting end-to-end ICM pilot plant was reported by CONTINUUS Pharmaceuticals in 2019 [12]. The throughput of the process was 4800 tablets per hour, or 40.3 × 10 6 tablets per year, with a total residence time of <30 h. There are examples of continuously manufactured drug products that have been approved in the US (e.g., Orkambi Johnson & Johnson, Verzenio by Eli Lilly), as well as drugs that are under development [12,16,19]. The reaction is one of the necessary steps in the continuous manufacturing of pharmaceuticals.…”
Section: Introductionmentioning
confidence: 99%
“…The model drug was aliskiren hemifumarate, and the throughput of the process was 45 g/h, with a residence time of 47 h. Subsequently, the first commercial-setting end-to-end ICM pilot plant was reported by CONTINUUS Pharmaceuticals in 2019 [ 12 ]. The throughput of the process was 4800 tablets per hour, or 40.3 × 10 6 tablets per year, with a total residence time of <30 h. There are examples of continuously manufactured drug products that have been approved in the US (e.g., Orkambi, Symdeko and Trikafta by Vertex, Prezista by Johnson & Johnson, Verzenio by Eli Lilly, Daurismo by Pfizer), in the EU (e.g., Orkambi and Symkevi by Vertex, Prezista by Johnson & Johnson, Verzenios by Eli Lilly), and in Japan (e.g., Tramacet by Johnson & Johnson, Verzenio by Eli Lilly), as well as drugs that are under development [ 12 , 16 , 19 ]. Fig.…”
Pharmaceutical production remains one of the last industries that predominantly uses batch processes, which are inefficient and can cause drug shortages due to the long lead times or quality defects. Consequently, pharmaceutical companies are transitioning away from outdated batch lines, in large part motivated by the many advantages of continuous manufacturing (e.g., low cost, quality assurance, shortened lead time). As chemical reactions are fundamental to any drug production process, the selection of reactor and its design are critical to enhanced performance such as improved selectivity and yield. In this article, relevant theories, and models, as well as their required input data are summarized to assist the reader in these tasks, focusing on continuous reactions. Selected examples that describe the application of plug flow reactors (PFRs) and continuous-stirred tank reactors (CSTRs)-in-series within the pharmaceutical industry are provided. Process analytical technologies (PATs), which are important tools that provide real-time in-line continuous monitoring of reactions, are recommended to be considered during the reactor design process (e.g., port design for the PAT probe). Finally, other important points, such as density change caused by thermal expansion or solid precipitation, clogging/fouling, and scaling-up, are discussed.
“…The model drug was aliskiren hemifumarate, and the throughput of the process was 45 g/h, with a residence time of 47 h. Subsequently, the first commercial-setting end-to-end ICM pilot plant was reported by CONTINUUS Pharmaceuticals in 2019 [12]. The throughput of the process was 4800 tablets per hour, or 40.3 × 10 6 tablets per year, with a total residence time of <30 h. There are examples of continuously manufactured drug products that have been approved in the US (e.g., Orkambi Johnson & Johnson, Verzenio by Eli Lilly), as well as drugs that are under development [12,16,19]. The reaction is one of the necessary steps in the continuous manufacturing of pharmaceuticals.…”
Section: Introductionmentioning
confidence: 99%
“…The model drug was aliskiren hemifumarate, and the throughput of the process was 45 g/h, with a residence time of 47 h. Subsequently, the first commercial-setting end-to-end ICM pilot plant was reported by CONTINUUS Pharmaceuticals in 2019 [ 12 ]. The throughput of the process was 4800 tablets per hour, or 40.3 × 10 6 tablets per year, with a total residence time of <30 h. There are examples of continuously manufactured drug products that have been approved in the US (e.g., Orkambi, Symdeko and Trikafta by Vertex, Prezista by Johnson & Johnson, Verzenio by Eli Lilly, Daurismo by Pfizer), in the EU (e.g., Orkambi and Symkevi by Vertex, Prezista by Johnson & Johnson, Verzenios by Eli Lilly), and in Japan (e.g., Tramacet by Johnson & Johnson, Verzenio by Eli Lilly), as well as drugs that are under development [ 12 , 16 , 19 ]. Fig.…”
Pharmaceutical production remains one of the last industries that predominantly uses batch processes, which are inefficient and can cause drug shortages due to the long lead times or quality defects. Consequently, pharmaceutical companies are transitioning away from outdated batch lines, in large part motivated by the many advantages of continuous manufacturing (e.g., low cost, quality assurance, shortened lead time). As chemical reactions are fundamental to any drug production process, the selection of reactor and its design are critical to enhanced performance such as improved selectivity and yield. In this article, relevant theories, and models, as well as their required input data are summarized to assist the reader in these tasks, focusing on continuous reactions. Selected examples that describe the application of plug flow reactors (PFRs) and continuous-stirred tank reactors (CSTRs)-in-series within the pharmaceutical industry are provided. Process analytical technologies (PATs), which are important tools that provide real-time in-line continuous monitoring of reactions, are recommended to be considered during the reactor design process (e.g., port design for the PAT probe). Finally, other important points, such as density change caused by thermal expansion or solid precipitation, clogging/fouling, and scaling-up, are discussed.
“…Several researchers have utilized commercially available software for flowsheet modeling purposes, e.g. (12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22). In general, the user constructs a flowsheet by connecting modules that represent various unit operations with material streams of prescribed properties.…”
Continuous manufacturing (CM) is an emerging technology which can improve pharmaceutical manufacturing and reduce drug product quality issues. One challenge that needs to be addressed when adopting CM technology is material traceability through the entire continuous process, which constitutes one key aspect of control strategy. Residence time distribution (RTD) play an important role in material traceability as it characterizes the material spreading through the process. The propagation of upstream disturbances could be predictively tracked through the entire process by convolution of the disturbance and the RTD. The present study sets up the RTD-based modeling framework in a commonly used process modeling environment, gPROMS, and integrates it with existing modules and built-in tools (e.g. parameter estimation). Concentration calculations based on the convolution integral requires access to historical stream property information, which is not readily available in flowsheet modeling platforms. Thus, a novel approach is taken whereby a partial differential equation is used to propagate and store historical data as the simulation marches forward in time. Other stream properties not modeled by an RTD are determined in auxiliary modules. To illustrate the application of the framework, an integrated RTD-auxiliary model for a continuous direct compression manufacturing line was developed. An excellent agreement was found between the model predictions and experiments. The validated model was subsequently used to assess in-process control strategies for feeder and material traceability through the process. Our simulation results show the employed modeling approach facilitates risk-based assessment of the continuous line by promoting our understanding on the process.
“…The preparation of a final product in different quantities than it is worked on during the research and development (R&D) process is expressed as -scale-up‖ or -scale-down‖. Generally, when we look at the pharmaceutical or cosmetic industry, R&D batch sizes are made in possible minor quantities 9 . For this reason, the concept of scale-up appears more frequently in these areas when transferring from R&D processes to mass production.…”
The perception of aesthetics directs the daily life of people from ancient times to the present. While the desire to be beautiful turns into a passion for some, it can also become a medical necessity for some people, such as war veterans. The historical documents examined show that both men and women use different materials to change their appearance and/or protect their skin. These materials still lead the way in the development of today's cosmetic products. The cosmetics industry is an important business line developed based on this aesthetic perception of societies.Starting from the research and development (R&D) process of a cosmetic formulation and becoming a final product, health authorities control the industry by various regulations. In this process, where each step must be meticulously fulfilled, perhaps the most critical step is the scale-up process. In this review, cosmetic products, scale-up and critical parameters in scale-up process are discussed.
Peer Review History:
Received: 7 May 2021; Revised: 16 June; Accepted: 23 June, Available online: 15 July 2021
Academic Editor: Dr. Ali Abdullah Al-yahawi, Al-Razi university, Department of Pharmacy, Yemen, alyahawipharm@yahoo.com
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Received file: Reviewer's Comments:
Average Peer review marks at initial stage: 6.5/10
Average Peer review marks at publication stage: 7.5/10
Reviewer(s) detail:
Dr. Salfarina Ramli, salfarina2892@uitm.edu.my Department of Pharmacology and Pharmaceutical Chemistry, Faculty of Pharmacy, Universiti Teknologi MARA, 42300 Puncak Alam, Selangor, Malaysia.
Dr. Govind Vyas, Compliance & Regulatory Officer Inva-Tech Pharmaceuticals LLC, New-Jersey, USA, govindvyas03@gmail.com
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