Advance in Pharmaceutical Engineering: PAT and Model-Based Approach for QbD and Continuous Processes

A special issue of Pharmaceutics (ISSN 1999-4923). This special issue belongs to the section "Pharmaceutical Technology, Manufacturing and Devices".

Deadline for manuscript submissions: closed (31 October 2022) | Viewed by 11935

Special Issue Editors


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Guest Editor
Coordinator of Pharmaceutical Technology lab, Department of Applied Science and Technology, Politecnico di Torino, 24 Corso Duca degli Abruzzi, 10129 Torino, Italy
Interests: freeze-drying; process monitoring; drug release; nanocarriers

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Guest Editor

E-Mail Website
Guest Editor
Molecular Engineering Laboratory, Department of Applied Science and Technology, Politecnico di Torino, 24 Corso Duca degli Abruzzi, 10129 Torino, Italy
Interests: freeze drying; freezing; proteins; molecular dynamics

Special Issue Information

Dear Colleagues,

The pharmaceutical industry is facing an unprecedented challenge in terms of market demand and volatility. This poses the problem of advancing the current system of production with new technologies capable of guaranteeing more flexibility, increased productivity, and operational excellence.

The aim of this Special Issue is to collect state-of-the-art knowledge in advanced technologies for pharmaceutical manufacturing. Special focus will be devoted to process analytical technologies (PAT), whose application enables higher yields and cost reduction through better process understanding. Contributions devoted to the development and application of modeling approaches for the design and control of pharmaceutical production, in the framework of the quality by design (QbD) concept, are also welcomed. A key point of the Special Issue is the potential application of PAT and model-based design to the development of continuous production processes, whose implementation would represent an important milestone towards a fully flexible, high-quality, and easily scalable production pipeline.

Topics include but are not limited to applications in the following areas:

  • Monitoring and optimization of production processes;
  • Non-invasive monitoring of freeze-drying process;
  • New trends in drying process of sensible products;
  • Continuous crystallization and freeze-drying;
  • Quality by design and model-based approaches.

Submission of original research work or review articles is equally welcome.

Prof. Dr. Antonello A. Barresi
Prof. Dr. Alberto Vallan
Dr. Andrea Arsiccio
Guest Editors

Manuscript Submission Information

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Keywords

  • freeze-drying
  • crystallization
  • tableting
  • continuous manufacturing
  • process analytical technology
  • process optimization
  • process control
  • quality by design
  • modelling

Published Papers (7 papers)

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Research

15 pages, 4405 KiB  
Article
The Freeze-Drying of Pharmaceuticals in Vials Nested in a Rack System—Part II: Primary Drying Behaviour
by Fiora Artusio, Marco Adami, Antonello A. Barresi, Davide Fissore, Maria Chiara Frare, Claudia I. Udrescu and Roberto Pisano
Pharmaceutics 2023, 15(11), 2570; https://doi.org/10.3390/pharmaceutics15112570 - 02 Nov 2023
Viewed by 996
Abstract
The freeze-drying of biopharmaceuticals is a common strategy to extend their shelf-life and facilitate the distribution of therapeutics. The drying phase is the most demanding one in terms of energy consumption and determines the overall process time. Our previous work showed how the [...] Read more.
The freeze-drying of biopharmaceuticals is a common strategy to extend their shelf-life and facilitate the distribution of therapeutics. The drying phase is the most demanding one in terms of energy consumption and determines the overall process time. Our previous work showed how the loading configuration can impact freezing. This paper focuses on primary drying by comparing the thermal behaviour of vials loaded in direct contact with the shelf or nested in a rack system. The overall heat transfer coefficient from the apparatus to the product was evaluated at different chamber pressures (5–30 Pa) and shelf temperatures (from −10 °C to +30 °C), and in the case of various vial positions (central, semi-border, and border vials). Because of the suspended configuration, the heat transfer coefficient was less affected by chamber pressure in vials nested in a rack system. The two loading configurations displayed comparable heat transfer efficiency below 10 Pa. For higher chamber pressure, the heat transfer coefficients of nested vials were lower than those of vials in direct contact with the shelf. Nevertheless, the rack system was beneficial for reducing the inter-vial variability as it promoted higher uniformity in the heat transfer coefficients of central vials. Eventually, thermal image analyses highlighted limited temperature differences between the vials and the rack system. Full article
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15 pages, 4330 KiB  
Article
Accelerated Production of Biopharmaceuticals via Microwave-Assisted Freeze-Drying (MFD)
by Nicole Härdter, Raimund Geidobler, Ingo Presser and Gerhard Winter
Pharmaceutics 2023, 15(5), 1342; https://doi.org/10.3390/pharmaceutics15051342 - 27 Apr 2023
Cited by 1 | Viewed by 1394
Abstract
Recently, attention has been drawn to microwave-assisted freeze-drying (MFD), as it drastically reduces the typically long drying times of biopharmaceuticals in conventional freeze-drying (CFD). Nevertheless, previously described prototype machines lack important attributes such as in-chamber freezing and stoppering, not allowing for the performance [...] Read more.
Recently, attention has been drawn to microwave-assisted freeze-drying (MFD), as it drastically reduces the typically long drying times of biopharmaceuticals in conventional freeze-drying (CFD). Nevertheless, previously described prototype machines lack important attributes such as in-chamber freezing and stoppering, not allowing for the performance of representative vial freeze-drying processes. In this study, we present a new technical MFD setup, designed with GMP processes in mind. It is based on a standard lyophilizer equipped with flat semiconductor microwave modules. The idea was to enable the retrofitting of standard freeze-dryers with a microwave option, which would reduce the hurdles of implementation. We aimed to collect process data with respect to the speed, settings, and controllability of the MFD processes. Moreover, we studied the performance of six monoclonal antibody (mAb) formulations in terms of quality after drying and stability after storage for 6 months. We found drying processes to be drastically shortened and well controllable and observed no signs of plasma discharge. The characterization of the lyophilizates revealed an elegant cake appearance and remarkably good stability in the mAb after MFD. Furthermore, overall storage stability was good, even when residual moisture was increased due to high concentrations of glass-forming excipients. A direct comparison of stability data following MFD and CFD demonstrated similar stability profiles. We conclude that the new machine design is highly advantageous, enabling the fast-drying of excipient-dominated, low-concentrated mAb formulations in compliance with modern manufacturing technology. Full article
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20 pages, 2380 KiB  
Article
On the Use of Temperature Measurements as a Process Analytical Technology (PAT) for the Monitoring of a Pharmaceutical Freeze-Drying Process
by Alberto Vallan, Davide Fissore, Roberto Pisano and Antonello A. Barresi
Pharmaceutics 2023, 15(3), 861; https://doi.org/10.3390/pharmaceutics15030861 - 07 Mar 2023
Cited by 3 | Viewed by 1272
Abstract
The measurement of product temperature is one of the methods that can be adopted, especially in the pharmaceutical industry, to monitor the freeze-drying process and to obtain the values of the process parameters required by mathematical models useful for in-line (or off-line) optimization. [...] Read more.
The measurement of product temperature is one of the methods that can be adopted, especially in the pharmaceutical industry, to monitor the freeze-drying process and to obtain the values of the process parameters required by mathematical models useful for in-line (or off-line) optimization. Either a contact or a contactless device and a simple algorithm based on a mathematical model of the process can be employed to obtain a PAT tool. This work deeply investigated the use of direct temperature measurement for process monitoring to determine not only the product temperature, but also the end of primary drying and the process parameters (heat and mass transfer coefficients), as well as evaluating the degree of uncertainty of the obtained results. Experiments were carried out with thin thermocouples in a lab-scale freeze-dryer using two different model products, sucrose and PVP solutions; they are representative of two types of commonly freeze-dried products, namely those whose structures are strongly nonuniform in the axial direction, showing a variable pore size with the cake depth and a crust (leading to a strongly nonlinear cake resistance), as well as those whose structures are uniform, with an open structure and, consequently, a cake resistance varying linearly with thickness. The results confirm that the model parameters in both cases can be estimated with an uncertainty that is in agreement with that obtained with other more invasive and expensive sensors. Finally, the strengths and weaknesses of the proposed approach coupled with the use of thermocouples was discussed, comparing with a case using a contactless device (infrared camera). Full article
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15 pages, 2425 KiB  
Article
Comparison of the Robustness of Pellet Film Coating with and without In-Process Coating Thickness Evaluation
by Teja Brezovar, Sandi Svetič and Rok Dreu
Pharmaceutics 2022, 14(11), 2274; https://doi.org/10.3390/pharmaceutics14112274 - 24 Oct 2022
Cited by 1 | Viewed by 1043
Abstract
The robustness of the pellet coating process with and without the use of an in-process coating thickness analyzer (PATVIS APA) was investigated. Pellets containing model drug were coated with a prolonged release film coating, using different process conditions. In the first set of [...] Read more.
The robustness of the pellet coating process with and without the use of an in-process coating thickness analyzer (PATVIS APA) was investigated. Pellets containing model drug were coated with a prolonged release film coating, using different process conditions. In the first set of experiments film coating was performed as process repetitions with unintentional variation of process parameters, and in the second set, controlled changes (inlet air humidity, gap between distribution plate and Wurster partition, starting pellet load) were made. Within the first set of experiments, the coating process endpoint was determined either via gravimetric consumption of coating dispersion or by means of in-line coating thickness monitoring. The release profiles of the pellets were analyzed and the density of coating calculated. Both methods of the process endpoint determination can be relatively robust in batch processing, if key factors influencing drug release profile are under control. PATVIS APA was shown to be a useful tool to better understand the coating process and can be helpful if coating process interruptions are encountered. Water content was shown to be the key factor influencing the drug profile, presumably by influencing the structure and thickness of the coating applied. Full article
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16 pages, 4800 KiB  
Article
The Influence of Local Microstructure Inhomogeneities on Local Drying Kinetics during Freeze-Drying
by Sebastian Gruber, Maximilian Thomik, Nicole Vorhauer-Huget, Lukas Hans, Evangelos Tsotsas and Petra Foerst
Pharmaceutics 2022, 14(10), 2132; https://doi.org/10.3390/pharmaceutics14102132 - 07 Oct 2022
Cited by 2 | Viewed by 1353
Abstract
Freeze-drying is a gentle drying technique to dry high value products, such as pharmaceuticals, without impacting the quality of the product. However, this method is very time and cost intensive. It is known that larger pores reduce the duration of primary drying due [...] Read more.
Freeze-drying is a gentle drying technique to dry high value products, such as pharmaceuticals, without impacting the quality of the product. However, this method is very time and cost intensive. It is known that larger pores reduce the duration of primary drying due to facilitated mass transport. However, next to the pore size, other structural parameters exist whose influence on drying kinetics is still unknown. Therefore, the aim of this article is to investigate the influence of the microstructure (pore size, shape and orientation) on local primary drying kinetics. In the study, freeze-drying experiments on maltodextrin and sucrose solutions (c1 = 0.05 and c2 = 0.15 w/w) were carried out in a lyomicroscope. Two-dimensional images were recorded during the whole drying process and in the dry state and analyzed on the movement of the sublimation front, pore size, orientation and shape. Different microstructures were created by using different freezing parameters, namely two different cooling rates and solid concentrations. It could be shown that for pores with a high aspect ratio, the pore orientation was more important for the drying kinetics than the pore size, while for pores with a lower aspect ratio the pore size was the decisive parameter. Full article
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17 pages, 5260 KiB  
Article
Model-Based Product Temperature and Endpoint Determination in Primary Drying of Lyophilization Processes
by Alex Juckers, Petra Knerr, Frank Harms and Jochen Strube
Pharmaceutics 2022, 14(4), 809; https://doi.org/10.3390/pharmaceutics14040809 - 07 Apr 2022
Cited by 8 | Viewed by 2065
Abstract
Lyophilization process design still relies mainly on empirical studies with high experimental loads. In the regulatory demanded Quality by Design approach, process modeling is a key aspect. It allows process design, optimization and process control to ensure a safe process and product quality. [...] Read more.
Lyophilization process design still relies mainly on empirical studies with high experimental loads. In the regulatory demanded Quality by Design approach, process modeling is a key aspect. It allows process design, optimization and process control to ensure a safe process and product quality. A modeling approach is outlined that is able to predict the primary drying endpoint and temperature profile of distinct vials. Model parameters are determined by a reproducible determination concept. Simulated results are validated with a fractional factorial Design of Experiments (DoE) in pilot scale. The model shows higher accuracy and precision than the experiments and similar parameter interactions for both the endpoint and temperature determination. This approach can now be used to explore the primary design space in lyophilization process design. This paper proposes a distinct method for endpoint determination and product temperature prediction by a modeling approach based on Velardi et al. combined with a distinct model parameter determination according to Wegiel et al. and Tang et al. Full article
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21 pages, 4269 KiB  
Article
QbD Consideration for Developing a Double-Layered Tablet into a Single-Layered Tablet with Telmisartan and Amlodipine
by Joo-Eun Kim and Young-Joon Park
Pharmaceutics 2022, 14(2), 377; https://doi.org/10.3390/pharmaceutics14020377 - 08 Feb 2022
Cited by 5 | Viewed by 2864
Abstract
The aim of this study was to develop a single-layered version of commercially available Twynstar® (Telmisartan + Amlodipine) double-layered tablets to improve the dosing convenience. A quality-by-design approach was applied to develop the single-layered version. To evaluate the range and cause of [...] Read more.
The aim of this study was to develop a single-layered version of commercially available Twynstar® (Telmisartan + Amlodipine) double-layered tablets to improve the dosing convenience. A quality-by-design approach was applied to develop the single-layered version. To evaluate the range and cause of risks for a single-layered tablet in the formulation design research, we used the tools of the risk assessment, initial risk assessment of preliminary hazard analysis and main risk assessment of failure mode and effect analysis to determine the parameters affecting formulation, drug dissolution, and impurities. The critical material attributes were the stabilizer and disintegrant, and the critical process parameters were the wet granulation and tableting process. The optimal range of the design space was determined using the central composite design in the wet granulation and tablet compression processes. The stabilizer, kneading time, and disintegrant of the wet granulation were identified as X values affecting Y values. The compression force and turret speed in the tablet compression were identified as X values affecting Y values. After deciding on the design space with the deduced Y values, the single-layered tablets were formulated, and their dissolution patterns were compared with that of the double-layered tablet. The selected quality-by-design (QbD) approach single-layered tablet formulated using design space were found to be bioequivalent to the Twynstar® double-layered tablets. Hence, the development of single-layered tablets with two API using the QbD approach could improve the medication compliance of patients and could be used as a platform to overcome time-consuming and excessive costs and the technical and commercial limitations related to various multi-layered tablets. Full article
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