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Schematic evolution of a Freeze-drying cycle. Adapted from (LyophilizationWorld, 2020).

Schematic evolution of a Freeze-drying cycle. Adapted from (LyophilizationWorld, 2020).

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In the past two decades, biopharmaceuticals have been a breakthrough in improving the quality of lives of patients with various cancers, autoimmune, genetic disorders etc. With the growing demand of biopharmaceuticals, the need for reducing manufacturing costs is essential without compromising on the safety, quality, and efficacy of products. Batch...

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... batch Freeze-drying process involves the removal of solvent, typically water, from a solution based on the principle of sublimation. A typical batch Freeze-dryer consists of a drying chamber with multiple shelves, a condenser and a vacuum pump. The process of Freeze-drying consists of 3 major steps: freezing, primary drying and secondary drying. Fig. 1 depicts a laboratory-scale Freeze-drying cycle. Vials containing the desired volume of liquid product are partially stoppered and loaded into the drying chamber. Freezing of the product is carried out at very low temperatures ranging between -40 to -60 • C to ensure solidification below the eutectic point (T m ) of crystalline ...
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... that have been inspected by the FDA and produced clinical supplies for phase 3 pivotal studies. The authors have demonstrated the use of Anhydro MS-35 Spray-dryer to successfully produce dry powder-based mAbs (Bowen et al., 2013;Gikanga et al., 2015). However, some of the factors that may induce instability in proteins have been depicted in Fig. 10. Fig. 10 represents a schematic diagram of the Spray-drying process using a cyclone-based separator. The liquid feed is drawn towards the spray nozzle at a flow rate using a peristaltic pump. With the help of an atomizing gas flow and desired size of spray nozzle orifice, the liquid is atomized and sprayed into the upper drying ...
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... have been inspected by the FDA and produced clinical supplies for phase 3 pivotal studies. The authors have demonstrated the use of Anhydro MS-35 Spray-dryer to successfully produce dry powder-based mAbs (Bowen et al., 2013;Gikanga et al., 2015). However, some of the factors that may induce instability in proteins have been depicted in Fig. 10. Fig. 10 represents a schematic diagram of the Spray-drying process using a cyclone-based separator. The liquid feed is drawn towards the spray nozzle at a flow rate using a peristaltic pump. With the help of an atomizing gas flow and desired size of spray nozzle orifice, the liquid is atomized and sprayed into the upper drying chamber. The ...
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... the impact of spraying conditions prior to dehydration, can provide more insight while developing and choosing excipients for Spray-drying proteins. Typically, the liquid feed is drawn into a twofluid nozzle at velocity, ν liq and exits the nozzle tip with a diameter, d i Fig. 9. LYnfinity® Production-Scale Spray-freeze-dryer (IMA Life, 2019). (Fig. 11). A resultant velocity, ν av is generated at the mixing zone with the help of an atomizing gas flow rate, ν gas . The shear rate generated from a two-fluid spray nozzle has been estimated using Equation (1) ( Ghandi et al., 2012;Hede et al., ...
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... for generating PRINT® particles reported by authors is discussed here ( Garcia et al., 2012;Gratton et al., 2007;Kelly and DeSimone, 2008). Perfluoropolyether (PFPE) was poured onto a prepared silicon master template containing the desired etching patterns of 2 µm, 5 µm and 200 nm sized shapes to produce a mould containing the same sized cavities (Fig. 12 (a)). Following the preparation of the PFPE mould, aqueous protein samples containing insulin, albumin and albumin mixtures with siRNA or paclitaxel were sandwiched between the cavities present in the mould and a high surface energy polyethylene film (Fig. 12 (b)). A pressure of 50 psi was applied through a roller to prevent the formation ...
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... 2 µm, 5 µm and 200 nm sized shapes to produce a mould containing the same sized cavities (Fig. 12 (a)). Following the preparation of the PFPE mould, aqueous protein samples containing insulin, albumin and albumin mixtures with siRNA or paclitaxel were sandwiched between the cavities present in the mould and a high surface energy polyethylene film (Fig. 12 (b)). A pressure of 50 psi was applied through a roller to prevent the formation of layers between the filled cavities and to laminate the samples present between the mould and the film (Fig. 12 (c)). Subsequently, the polyethylene film was removed and the mould containing the samples was Freeze-dried ( Fig. 12 (d)). The dehydration ...
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... and albumin mixtures with siRNA or paclitaxel were sandwiched between the cavities present in the mould and a high surface energy polyethylene film (Fig. 12 (b)). A pressure of 50 psi was applied through a roller to prevent the formation of layers between the filled cavities and to laminate the samples present between the mould and the film (Fig. 12 (c)). Subsequently, the polyethylene film was removed and the mould containing the samples was Freeze-dried ( Fig. 12 (d)). The dehydration process can also occur through either photocuring, vitrification or evaporation ( Xu et al., 2013). A liquid harvesting layer, made of either polycyano acrylate (PCA) or polyvinyl pyrrolidinone (PVP), ...
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... surface energy polyethylene film (Fig. 12 (b)). A pressure of 50 psi was applied through a roller to prevent the formation of layers between the filled cavities and to laminate the samples present between the mould and the film (Fig. 12 (c)). Subsequently, the polyethylene film was removed and the mould containing the samples was Freeze-dried ( Fig. 12 (d)). The dehydration process can also occur through either photocuring, vitrification or evaporation ( Xu et al., 2013). A liquid harvesting layer, made of either polycyano acrylate (PCA) or polyvinyl pyrrolidinone (PVP), was casted onto a glass slide (Fig. 12 (e)). Post Freeze-drying, the PFPE mould was placed over the adhesive ...
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... polyethylene film was removed and the mould containing the samples was Freeze-dried ( Fig. 12 (d)). The dehydration process can also occur through either photocuring, vitrification or evaporation ( Xu et al., 2013). A liquid harvesting layer, made of either polycyano acrylate (PCA) or polyvinyl pyrrolidinone (PVP), was casted onto a glass slide (Fig. 12 (e)). Post Freeze-drying, the PFPE mould was placed over the adhesive harvesting film (Fig. 12 (f)). Once the harvesting layer was dried, the PFPE mould was removed yielding dried protein particles onto the adhesive film (Fig. 12 (g)). Finally, freeflowing protein powder was recovered by dissolving the adhesive film ( Fig. 12 (h and i)). ...
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... (d)). The dehydration process can also occur through either photocuring, vitrification or evaporation ( Xu et al., 2013). A liquid harvesting layer, made of either polycyano acrylate (PCA) or polyvinyl pyrrolidinone (PVP), was casted onto a glass slide (Fig. 12 (e)). Post Freeze-drying, the PFPE mould was placed over the adhesive harvesting film (Fig. 12 (f)). Once the harvesting layer was dried, the PFPE mould was removed yielding dried protein particles onto the adhesive film (Fig. 12 (g)). Finally, freeflowing protein powder was recovered by dissolving the adhesive film ( Fig. 12 (h and i)). SEM images of the uniquely shape powders are shown in Fig. ...
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... layer, made of either polycyano acrylate (PCA) or polyvinyl pyrrolidinone (PVP), was casted onto a glass slide (Fig. 12 (e)). Post Freeze-drying, the PFPE mould was placed over the adhesive harvesting film (Fig. 12 (f)). Once the harvesting layer was dried, the PFPE mould was removed yielding dried protein particles onto the adhesive film (Fig. 12 (g)). Finally, freeflowing protein powder was recovered by dissolving the adhesive film ( Fig. 12 (h and i)). SEM images of the uniquely shape powders are shown in Fig. ...
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... onto a glass slide (Fig. 12 (e)). Post Freeze-drying, the PFPE mould was placed over the adhesive harvesting film (Fig. 12 (f)). Once the harvesting layer was dried, the PFPE mould was removed yielding dried protein particles onto the adhesive film (Fig. 12 (g)). Finally, freeflowing protein powder was recovered by dissolving the adhesive film ( Fig. 12 (h and i)). SEM images of the uniquely shape powders are shown in Fig. ...
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... placed over the adhesive harvesting film (Fig. 12 (f)). Once the harvesting layer was dried, the PFPE mould was removed yielding dried protein particles onto the adhesive film (Fig. 12 (g)). Finally, freeflowing protein powder was recovered by dissolving the adhesive film ( Fig. 12 (h and i)). SEM images of the uniquely shape powders are shown in Fig. ...
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... it. The micropipette was then positioned back into the organic chamber, releasing a single droplet of the protein solution which was held firmly at the tip of the micropipette in the organic chamber. By doing so, water from the single droplet was extracted into the organic chamber, thereby, leading to the formation of a Microglassified TM bead (Fig. ...
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... authors assumed similar low levels of residual moisture, as both Microglassified TM and Freeze-dried lysozyme absorbed the same amount of water as a function of water activity. Furthermore, the potential to Microglassify TM a recombinant biopolymer -elastin-like polypeptide (ELP) with controlled size and morphology for chemotherapy has been shown (Aniket et al., 2015b). More recently, this technique has seen application in the fabrication of biolasers for biosensing and optical device implantation purposes (Nguyen et al., 2019;Nguyen and Ta, 2020). ...
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... to any changes in the manufacturer's manufacturing process requires the evaluation of the impact of an alternative process on the safety, quality and efficacy of biopharmaceutical products (ICH, 2004). Any aberrations in the CQAs of biopharmaceutical products post drying can be assessed using various analytical and characterization techniques. Fig. 15 shows a comprehensive list of techniques currently employed to study some of the product CQAs in the solid and liquidstate. Some of these techniques are not employed for routine analyses but can provide additional information in understanding the impact of CPPs on product ...
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... spectroscopy have allowed researchers to study intricate information in the lower vacuum ultraviolet (VUV) region (<190 nm) using SRCD spectroscopy ( Miles et al., 2008;Wallace, 2020, 2006;Wallace, 2019Wallace, , 2009Wallace et al., 2004). SRCD has also seen application in protein photostability, Overall, the characterization techniques listed in Fig. 15 may have certain merits and demerits on their own but if employed as complimentary techniques, they can provide further insights on biopharmaceutical stability. These characterization techniques combined with different drying technologies can help the biopharmaceutical industry in choosing appropriate methods for manufacturing and ...
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... can significantly protect biopharmaceuticals at higher temperatures during Spray-drying due to its high glass transition temperature (>100 • C) ( Liao et al., 2004;Massant et al., 2020;Simperler et al., 2006). Authors have demonstrated that while sucrose preserves the protein's secondary structure during dehydration, trehalose provides protection during long-term storage of Freeze-dried and Spraydried lysozyme (Starciuc et al., 2019). Apart from disaccharides, cyclodextrin is widely used in Spray-dried protein formulations ( Pinto et al., 2021). ...

Citations

... Proteins in solution are more prone to chemical and physical degradation processes which are hydrolytically driven [18]. They also require the cold chain which is a formidable logistical challenge that adds to the high costs of producing mAbs [19]. Thus, another benefit of formulating thermosensitive proteins into dry powders is the ease of transport and storage. ...
... In spray freeze drying, some product was lost likely due to the retention of residual feed solution in the syringe and feeding tube. Nevertheless, spray drying is a more established and popular drying technology than spray freeze drying for industrial scale production [19,52,53]. ...
Article
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Objective The therapeutic options for severe asthma are limited, and the biological therapies are all parenterally administered. The purpose of this study was to formulate a monoclonal antibody that targets the receptor for IL-4, an interleukin implicated in the pathogenesis of severe asthma, into a dry powder intended for delivery via inhalation. Methods Dehydration was achieved using either spray drying or spray freeze drying, which exposes the thermolabile biomacromolecules to stresses such as shear and adverse temperatures. 2-hydroxypropyl-beta-cyclodextrin was incorporated into the formulation as protein stabiliser and aerosol performance enhancer. The powder formulations were characterised in terms of physical and aerodynamic properties, while the antibody was assessed with regard to its structural stability, antigen-binding ability, and in vitro biological activity after drying. Results The spray-freeze-dried formulations exhibited satisfactory aerosol performance, with emitted fraction exceeding 80% and fine particle fraction of around 50%. The aerosolisation of the spray-dried powders was hindered possibly by high residual moisture. Nevertheless, the antigen-binding ability and inhibitory potency were unaffected for the antibody in the selected spray-dried and spray-freeze-dried formulations, and the antibody was physically stable even after one-year storage at ambient conditions. Conclusions The findings of this study establish the feasibility of developing an inhaled dry powder formulation of an anti-IL-4R antibody using spray drying and spray freeze drying techniques with potential for the treatment of severe asthma.
... In contrast, spray drying is an enabling particle engineering technique, used to manufacture respirable particles of both small and large molecule active pharmaceutical ingredients (API) in a single-unit operation [7][8][9]. Spray drying as a pharmaceutical manufacturing technique has been reviewed extensively elsewhere [10,11]. Briefly, actives and excipients are co-dissolved in a volatile solvent and then atomized into droplets that are sprayed into a drying chamber. ...
Article
Full-text available
Spray drying is a particle engineering technique used to manufacture respirable pharmaceutical powders that are suitable for delivery to the deep lung. It is amenable to processing both small molecules and biologic actives, including proteins. In this work, a simultaneous spray-drying process, termed simul-spray, is described; the process involves two different active pharmaceutical ingredient (API) solutions that are simultaneously atomized through separate nozzles into a single-spray dryer. Collected by a single cyclone, simul-spray produces a uniform mixture of two different active particles in a single-unit operation. While combination therapies for dry powder inhalers containing milled small molecule API are commercially approved, limited options exist for preparing combination treatments that contain both small molecule APIs and biotherapeutic molecules. Simul-spray drying is also ideal for actives which cannot withstand a milling-based particle engineering process, or which require a high dose that is incompatible with a carrier-based formulation. Three combination case studies are demonstrated here, in which bevacizumab is paired with erlotinib, cisplatin, or paclitaxel in a dry powder inhaler formulation. These model systems were chosen for their potential relevance to the local treatment of lung cancer. The resulting formulations preserved the biologic activity of the antibody, achieved target drug concentration, and had aerosol properties suitable for pulmonary delivery.
Article
This study addressed the need for a flexible (personalizable) production of biologics, allowing their stabilization in the solid state and processing of small batch volumes. Therefore, inkjet printing into vials followed by a gentle vacuum drying step at ambient temperature was investigated by screening different formulations with a 22-full factorial design of experiments regarding printability. Human Serum Albumin (HSA) was used as a model protein in a wide range of concentrations (5 to 50 mg/ml), with (10 w/v%) and without the surfactant polysorbate80 (PS80). PS80 was identified to positively affect the formulations by increasing the Ohnesorge number and stabilizing the printing process. The dispensed volumes with a target dose of 0.5mg HSA were dried and analyzed concerning their residual moisture (RM) and protein aggregation. All investigated formulations showed an RM <10wt.% and no significant induced protein aggregation as confirmed by Size Exclusion Chromatography (< 2.5%) and Dynamic Light Scattering (Aggregation Index ≤ 2.5). Additionally, long-term printability and the available final dose after reconstitution were investigated for two optimized formulations. A promising formulation providing ∼93% of the targeted dose and a reconstitution time of 30s was identified.
Article
The inability of many biopharmaceutical formulations to retain their structure and integrity when in solution represents a major issue for their transport and storage, reducing their shelf-life and activity/stability. The ability to efficiently produce dried solid dosage forms of biopharmaceuticals such as proteins and nucleic acids allows for many improvements in the way in which these sensitive materials are stored, transported, and administered. While freeze-drying is an established drying method implemented in the biopharmaceutical industry with well-understood challenges, there has been a distinct lack of uptake in the development and usage of spray drying and supercritical fluid drying. These technologies typically provide distinct particles sizes and morphologies, introducing an additional route to improve the final product performance. This review focuses on the key aspects of various supercritical fluid methods reported in the literature to produce dried biopharmaceutical powders with enhanced stability compared to those produced by more conventional methods.