Process cycle development of freeze drying for therapeutic proteins with stability evaluation

Lim, Jun Yeul; Kim, Nam Ah; Lim, Dae Gon; Kim, Ki‐Hyun; Choi, Du Hyung; Jeong, Seong Hoon

doi:10.1007/s40005-016-0275-7

Cited by 31 publications

(19 citation statements)

References 101 publications

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“…Freeze-dried proteins have greater storage stability than proteins in liquid dosage forms; however, this process applies freezing and dehydration stresses to the proteins, which may result in the alteration of protein structure [ 31 , 32 , 33 ]. Upon drying, the hydration shell surrounding the protein, which provides a protective effect, is removed.…”

Section: Drying Techniquesmentioning

confidence: 99%

“…In addition, the protein solution becomes saturated because of ice crystal formation during the freezing process. The solute concentration, pH change, and ionic strength changes are formulation variables that should be considered for a stable protein formulation ( Table 1 ) [ 1 , 33 ]. Recent infrared spectroscopic analyses have shown that acute freezing and dehydration stresses of lyophilization can induce protein unfolding [ 29 , 34 ].…”

Section: Drying Techniquesmentioning

confidence: 99%

“…Intact cakes have very low residual moisture content with great long-term stability. FD powders of protein formulations after reconstitution can be used for parenteral drug delivery [ 33 ]. However, the use of FD for particle-based formulations, such as those for pulmonary drug delivery, is limited because it is not a direct particle formation method [ 37 ].…”

Section: Drying Techniquesmentioning

confidence: 99%

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Drying Technologies for the Stability and Bioavailability of Biopharmaceuticals

et al. 2018

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Solid dosage forms of biopharmaceuticals such as therapeutic proteins could provide enhanced bioavailability, improved storage stability, as well as expanded alternatives to parenteral administration. Although numerous drying methods have been used for preparing dried protein powders, choosing a suitable drying technique remains a challenge. In this review, the most frequent drying methods, such as freeze drying, spray drying, spray freeze drying, and supercritical fluid drying, for improving the stability and bioavailability of therapeutic proteins, are discussed. These technologies can prepare protein formulations for different applications as they produce particles with different sizes and morphologies. Proper drying methods are chosen, and the critical process parameters are optimized based on the proposed route of drug administration and the required pharmacokinetics. In an optimized drying procedure, the screening of formulations according to their protein properties is performed to prepare a stable protein formulation for various delivery systems, including pulmonary, nasal, and sustained-release applications.

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Section: Drying Techniquesmentioning

confidence: 99%

Section: Drying Techniquesmentioning

confidence: 99%

Section: Drying Techniquesmentioning

confidence: 99%

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Drying Technologies for the Stability and Bioavailability of Biopharmaceuticals

et al. 2018

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“…Thus, freeze-drying to generate lyophilized preparations represents a reference process for the manufacturing of high-quality drug products with appropriate stability for long-term storage (Lim et al 2016). The final drug formulation before the freeze drying process needs to provide protein stability through all the stresses imposed during the freeze drying process, long-term storage and reconstitution (Jameel and Pikal 2010).…”

Section: Introductionmentioning

confidence: 99%

Investigations into, and development of, a lyophilized and formulated recombinant human factor IX produced from CHO cells

et al. 2017

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Objectives To develop a recombinant FIX (rFIX) formulation equivalent to commercially available products in terms of cake appearance, residual moisture, proportion of soluble aggregates and activity maintenance for 3 months at 4-8°C.Results NaCl and low bulking agent/cryoprotectant mass ratio had a negative impact on cake quality upon lyophilisation, for a wide range of formulations tested. Particular devised formulations were able to maintain rFIX activity after lyophilization with a similar performance when compared with the rFIX formulated using the excipients reported for a commercially available FIX formulation (Benefix®). The stability study showed that rFIX remained active after 3 months when stored at 4°C, though this was not the case with samples stored at 40°C.Interestingly, particular formulations were found to show an increase in residual moisture after 3 months storage, but not above a 3% threshold. All four formulations tested were equivalent to the Benefix® formulation in terms of particle size distribution and cake appearance.Conclusions Three specific formulations, consisting of surfactant polysorbate-80, sucrose or trehalose as cryoprotectant, mannitol or glycine as bulking agent, L-histidine as buffering agent, and NaCl added in the reconstitution liquid at a 0.234% (w/v) concentration appear suitable for use with a CHO cell derived recombinant FIX.

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“…6,7 Therefore, freeze-drying is often used to prepare the solid formulation of pharmaceutical proteins and retain the long-term stability of various proteins. 3,8,9 However, water is also critical in maintaining the folding structures of proteins. During folding, nonpolar amino acids are located toward the inner core of the molecule while the residues with polar side chains are predominately located toward the outer surface.…”

Section: Introductionmentioning

confidence: 99%

Biophysical evaluation of aminoclay as an effective protectant for protein stabilization during freeze-drying and storage

Song

Lee

Han

2016

IJN

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This study aimed to evaluate aminoclay (3-aminopropyl-functionalized magnesium phyllosilicate) as an effective protectant for the stabilization of protein formulation in freeze-drying. Bovine serum albumin (BSA), as a model protein, was freeze-dried with aminoclay at various concentrations, and the effects of aminoclay on the structural stability of proteins were compared with those of the conventional stabilizers. The structural characteristics of the protein were determined by size exclusion chromatography (SEC), circular dichroism (CD), and Fourier transform infrared (FTIR) spectroscopy. Furthermore, physicochemical and morphological characteristics were examined by X-ray powder diffraction (XRPD), differential scanning calorimetry (DSC), and scanning electron microscopy (SEM). XRPD and DSC patterns indicated that the glass transition temperature (Tg) of the amorphous formulation of aminoclay mixed with proteins was gradually elevated as the concentration of aminoclay increased. FTIR and CD spectral analysis suggested that the protein structure was well maintained with aminoclay during the freeze-drying process and 3 months of storage at 4°C and 40°C. Furthermore, aminoclay conferred the greatest protection against aggregation and retained the monomer content of BSA even at a high temperature. The morphological characteristics of lyophilized proteins were also well conserved during the storage with aminoclay. These results suggested that aminoclay may be useful as an alternative stabilizer for maintaining the structural stability of protein formulations.

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Process cycle development of freeze drying for therapeutic proteins with stability evaluation

Cited by 31 publications

References 101 publications

Drying Technologies for the Stability and Bioavailability of Biopharmaceuticals

Drying Technologies for the Stability and Bioavailability of Biopharmaceuticals

Investigations into, and development of, a lyophilized and formulated recombinant human factor IX produced from CHO cells

Biophysical evaluation of aminoclay as an effective protectant for protein stabilization during freeze-drying and storage

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