Effects of cooling rate in microscale and pilot scale freeze-drying – Variations in excipient polymorphs and protein secondary structure

Peters, Björn-Hendrik; Staels, Lotte; Rantanen, Jimi; Molnár, Ferdinand; Beer, Thomas De; Lehto, Vesa‐Pekka; Ketolainen, Jarkko

doi:10.1016/j.ejps.2016.05.020

Cited by 33 publications

(15 citation statements)

References 32 publications

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“…The height of this peak was similar to the T OFS peaks obtained for the amorphous sugar systems (Figure 5A ). DSC scans of the mannitol solution rendered two Tg' values in the same temperature range with Tg' 1 : −29.5 ± 0.2°C and Tg' 2 : −24.1 ± 0.9°C (Figure 5B ) which corresponded to literature (Cavatur et al, 2002 ; Hawe and Frieß, 2006 ; Peters et al, 2016 ). Thus, the OFS peak can be assigned to an increased viscous flow of the amorphous mannitol fraction.…”

Section: Resultssupporting

confidence: 85%

“…Typically, crystallinity is analyzed in the lyophilized product by X-ray powder diffraction, DSC measurements, NIR—or Raman spectroscopy (Shah et al, 2006 ). Mannitol crystallization upon freeze-drying was thoroughly investigated with these methods (Johnson et al, 2002 ; Liao et al, 2005 , 2007 ; Hawe and Frieß, 2006 ; De Beer et al, 2007 , 2009 ; Jena et al, 2016 , 2017 ; Peters et al, 2016 ). Kasper et al already observed a small peak in OFS thermograms of 5% mannitol solutions during freezing and assigned it as mannitol crystallization (Kasper et al, 2013 ).…”

Section: Resultsmentioning

confidence: 99%

“…Nevertheless, since it is known that an 1°C increase in Tp can shorten primary drying times by about 13%, the interest is to dry at the highest possible Tp (Pikal, 1990 ). Crystalline bulking agents like mannitol not necessarily stabilize proteins but form crystalline scaffolds that provide robust and elegant cake structures (Johnson et al, 2002 ; Hawe and Frieß, 2006 ; Varshney et al, 2007 ; Peters et al, 2016 ). Their controlled and complete crystallization during the freeze-drying process is of interest since partial crystallization might induce subsequent crystallization of the amorphous fraction during storage leading to potential loss of drug stability (Izutsu and Kojima, 2002 ).…”

Section: Introductionmentioning

confidence: 99%

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Detection of Collapse and Crystallization of Saccharide, Protein, and Mannitol Formulations by Optical Fibers in Lyophilization

Horn

Frieß

2018

Front. Chem.

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The collapse temperature (Tc) and the glass transition temperature of freeze-concentrated solutions (Tg') as well as the crystallization behavior of excipients are important physicochemical characteristics which guide the cycle development in freeze-drying. The most frequently used methods to determine these values are differential scanning calorimetry (DSC) and freeze-drying microscopy (FDM). The objective of this study was to evaluate the optical fiber system (OFS) unit as alternative tool for the analysis of Tc, Tg' and crystallization events. The OFS unit was also tested as a potential online monitoring tool during freeze-drying. Freeze/thawing and freeze-drying experiments of sucrose, trehalose, stachyose, mannitol, and highly concentrated IgG1 and lysozyme solutions were carried out and monitored by the OFS. Comparative analyses were performed by DSC and FDM. OFS and FDM results correlated well. The crystallization behavior of mannitol could be monitored by the OFS during freeze/thawing as it can be done by DSC. Online monitoring of freeze-drying runs detected collapse of amorphous saccharide matrices. The OFS unit enabled the analysis of both Tc and crystallization processes, which is usually carried out by FDM and DSC. The OFS can hence be used as novel measuring device. Additionally, detection of these events during lyophilization facilitates online-monitoring. Thus the OFS is a new beneficial tool for the development and monitoring of freeze-drying processes.

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Section: Resultssupporting

confidence: 85%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Detection of Collapse and Crystallization of Saccharide, Protein, and Mannitol Formulations by Optical Fibers in Lyophilization

Horn

Frieß

2018

Front. Chem.

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“…However, the quench-frozen samples containing cryoprotectants, and in the absence of surfactants, all showed an increase in protein recovery compared with the buffer only formulation, and behaved very similarly, suggesting that mannitol did not crystallize under these conditions, in line with previous observations. 24,25 This effect of cryoprotectants and surfactants was not explicitly discussed in the simulation part of this work but could be included in the model by modifying the value of m in Equations 3 and 6 or the adsorption behavior at the ice interface (in the case of surfactants, Eq. 10).…”

Section: Comparison With Experimental Datamentioning

confidence: 99%

“…17,18 A faster cooling rate may also help prevent crystallization of buffering species, thus minimizing pH changes during freezing, 19,20 and could affect the extent of crystallization of excipients, the polymorph composition changes during the lyophilization process, or the final polymorph compositions. [21][22][23][24][25] The extension of the ice-water surface is also strongly influenced by the nucleation temperature, with a higher nucleation temperature resulting in larger crystals. 26 The thawing rate may also be crucial, as slow thawing promotes the recrystallization process, where small ice crystals grow into larger ones.…”

Section: Introductionmentioning

confidence: 99%

Considerations on Protein Stability During Freezing and Its Impact on the Freeze-Drying Cycle: A Design Space Approach

Arsiccio

Giorsello

Marenco

et al. 2020

Journal of Pharmaceutical Sciences

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Freezing is widely used during the manufacturing process of protein-based therapeutics, but it may result in undesired loss of biological activity. Many variables come into play during freezing that could adversely affect protein stability, creating a complex landscape of interrelated effects. The current approach to the selection of freezing conditions is however nonsystematic, resulting in poor process control. Here we show how mathematical models, and a design space approach, can guide the selection of the optimal freezing protocol, focusing on protein stability. Two opposite scenarios are identified, suggesting that the ice-water interface is the dominant cause of denaturation for proteins with high bulk stability, while the duration of the freezing process itself is the key parameter to be controlled for proteins that are susceptible to cold denaturation. Experimental data for lactate dehydrogenase and myoglobin as model proteins support the model results, with a slow freezing rate being optimal for lactate dehydrogenase and the opposite being true for myoglobin. A possible application of the calculated design space to the freezing and freeze-drying of biopharmaceuticals is finally described, and some considerations on process efficiency are discussed as well.

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Process Development of Protein Therapeutics

Huang¹,

Bowes²,

Yang³

et al. 2021

Burger's Medicinal Chemistry and Drug Discovery

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The application of recombinant DNA technology to the production of protein therapeutics has undergone tremendous progress over the past decades. Considerable scientific effort has been devoted to developing robust processes that produce large amounts of complex proteins with the desired product quality attributes. An overview of the contributions from the four major disciplines working in concert to deliver these processes and methods will be covered. This article will discuss some of the tools, methods, and approaches used to produce, purify, formulate, and analyze the drugs of modern biotechnology. Future trends in each of the disciplines will also be presented.

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Effects of cooling rate in microscale and pilot scale freeze-drying – Variations in excipient polymorphs and protein secondary structure

Cited by 33 publications

References 32 publications

Detection of Collapse and Crystallization of Saccharide, Protein, and Mannitol Formulations by Optical Fibers in Lyophilization

Detection of Collapse and Crystallization of Saccharide, Protein, and Mannitol Formulations by Optical Fibers in Lyophilization

Considerations on Protein Stability During Freezing and Its Impact on the Freeze-Drying Cycle: A Design Space Approach

Process Development of Protein Therapeutics

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