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Pharmaceutics
Special Issues
The Role of Freeze-Drying in Biopharmaceutical Manufacturing: Stability and Efficacy
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The Role of Freeze-Drying in Biopharmaceutical Manufacturing: Stability and Efficacy

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

Deadline for manuscript submissions: 30 January 2026 | Viewed by 1311

Special Issue Editors

Prof. Dr. Wei-Jie Fang

E-Mail Website
Guest Editor
College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China
Interests: biopharmaceutical formulation and process development; biopharmaceutical quality control and characterization; protein chemistry and high order structure analysis
Prof. Dr. Holger Grohganz

E-Mail Website
Guest Editor
Department of Pharmacy, University of Copenhagen, 2100 Copenhagen, Denmark
Interests: freeze-drying and spray-drying; co-amorphous systems; process analytical technology and quality by design; peptides and proteins in pharmaceutical formulations
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

We are pleased to invite you to submit original research articles or reviews to the Special Issue “The Role of Freeze-Drying in Biopharmaceutical Manufacturing: Stability and Efficacy”.

Biopharmaceuticals including monoclonal antibodies (mAbs), recombinant protein therapeutics, vaccines, and cellular and gene therapies (CGTs) are becoming new therapeutical modalities for the treatment and prevention of a variety of diseases over the past several decades. However, biopharmaceuticals are generally of marginal stability, and therefore, maintaining their structural and functional integrity is of paramount importance. Freeze-drying (FD) is the most widely employed drying technique to improve their stability. However, biopharmaceuticals are exposed to various stresses during the freeze-drying process (i.e., freezing, primary drying, and secondary drying). Therefore, the optimization of both the formulation and process variables is required.

This Special Issue aims to collect recent advances and applications of FD in biopharmaceutical manufacturing, mainly focusing on formulation and process optimization, as well as analytical technologies for processes and products. In this Special Issue, original research articles and reviews are welcome. Research areas may include (but are not limited to) the following:

  • Current challenges and future opportunities in the FD of biopharmaceuticals;
  • Development and optimization of FD formulations for biopharmaceuticals;
  • Development and optimization of FD processes for biopharmaceuticals;
  • FD process scale-up, technology transfer, and validation;
  • Quality risk management for change management;
  • Process analytical technology (PAT) for FD;
  • Technologies for the characterization of the physical matrix and the biopharmaceuticals in the solid state.

We look forward to receiving your contributions.

Prof. Dr. Wei-Jie Fang
Prof. Dr. Holger Grohganz
Guest Editors

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 250 words) can be sent to the Editorial Office for assessment.

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. Pharmaceutics 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 2900 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

  • freeze-drying
  • biopharmaceuticals
  • process scale-up, technology transfer, and validation
  • process analytical technology
  • analytical techniques for FD products

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Published Papers (2 papers)

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22 pages, 3198 KB  
Article
The Detrimental Effects of Crystalline Excipients: How They Jeopardize the Long-Term Stability of Freeze-Dried Polypeptide Formulations
by Han Gao, Jun Ouyang, Zhi-Bo Hu and Wei-Jie Fang
Pharmaceutics 2025, 17(12), 1543; https://doi.org/10.3390/pharmaceutics17121543 - 29 Nov 2025
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Abstract
Background: Despite the growing importance of polypeptide-based drugs in clinical therapy, studies investigating the stability of their freeze-dried formulations remain scarce. Crystalline excipients, such as mannitol, are commonly used in freeze-dried formulations of chemically synthesized drugs, but they often negatively impact the [...] Read more.
Background: Despite the growing importance of polypeptide-based drugs in clinical therapy, studies investigating the stability of their freeze-dried formulations remain scarce. Crystalline excipients, such as mannitol, are commonly used in freeze-dried formulations of chemically synthesized drugs, but they often negatively impact the long-term stability of biological macromolecules like monoclonal antibodies (mAbs). This study bridges this knowledge gap by evaluating the effects of crystalline and amorphous excipients, surfactants, and amino acid-based stabilizers on the long-term stability of freeze-dried formulations using model polypeptides, glucagon and insulin. Methods: The freeze-dried formulations were prepared with crystalline and amorphous excipients, surfactants, and amino acid-based stabilizers. The crystallization behavior of the excipients and the thermal stability of the formulations were thoroughly characterized using X-ray powder diffraction (XRPD) and differential scanning calorimetry (DSC). Results: The crystallization of mannitol was directly correlated with a significant reduction in the long-term stability of both model polypeptides. This detrimental effect mirrors the instability observed in mAbs formulations, indicating a common mechanism of protein destabilization induced by crystalline excipients, independent of molecular size. Conclusions: This study provides the first direct evidence that crystalline excipients pose a significant risk to the stability of freeze-dried polypeptides. These findings offer critical insights for the rational design of stable freeze-dried formulations, guiding industrial development strategies for polypeptide-based therapeutics. Full article
(This article belongs to the Special Issue The Role of Freeze-Drying in Biopharmaceutical Manufacturing: Stability and Efficacy)
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22 pages, 4663 KB  
Article
An Application for Through-Vial Impedance Spectroscopy (TVIS) in the Qualification of the Pirani-Gauge Assessment of the Ice Sublimation Endpoint
by Pathum Subash Wijesekara, Kiran Malik, Paul Matejtschuk and Geoff Smith
Pharmaceutics 2025, 17(12), 1542; https://doi.org/10.3390/pharmaceutics17121542 - 29 Nov 2025
Viewed by 303
Abstract
Background/Objectives: All the industry standard methods for monitoring the freeze-drying process, from the single-vial assessment using temperature probes, such as thermocouples, to batch assessments using comparative pressure measurements, have poorly defined transitions marking the end of ice sublimation. In this study, through-vial impedance [...] Read more.
Background/Objectives: All the industry standard methods for monitoring the freeze-drying process, from the single-vial assessment using temperature probes, such as thermocouples, to batch assessments using comparative pressure measurements, have poorly defined transitions marking the end of ice sublimation. In this study, through-vial impedance spectroscopy (TVIS) is used to characterise and validate the point on the Pirani curve that corresponds to the end of ice sublimation. The impact of the solution composition in relation to its propensity to form crystalline and amorphous domains and the impact of the batch size were investigated. Methods: Individual TVIS vials were placed at specific positions across the shelf, in order to represent the core and edge vials of the batch. The unique features of the high-frequency real part capacitance, with its precise sublimation endpoint-defining plateau, were then used to map the individual-vial sublimation endpoints onto the Pirani profile, with a view to predicting the batch sublimation endpoint. Results: TVIS vial endpoints enabled a key observation that the shape of the Pirani profile may be analysed in terms of two phases, the first being largely associated with ice sublimation and the second being associated with water desorption. Moreover, by identifying the transition point more precisely, even in the small to intermediate scale systems, we provide a scientific basis for predicting the sublimation endpoint for production-scale dryers, where Pirani sensors are already in place. Conclusions: Such qualification of batch sublimation endpoints would allow for earlier, confident switching to the secondary drying stage without unnecessary delay, leading to shorter cycles, reduced energy consumption, and improved utilisation of costly freeze-drying infrastructure. Full article
(This article belongs to the Special Issue The Role of Freeze-Drying in Biopharmaceutical Manufacturing: Stability and Efficacy)
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