Systematic investigation of the effect of lyophilizate collapse on pharmaceutically relevant proteins I: Stability after freeze‐drying

Schersch, Kathrin; Betz, O.; Garidel, Patrick; Muehlau, Silke; Bassarab, Stefan; Winter, Gerhard

doi:10.1002/jps.22000

Cited by 110 publications

(72 citation statements)

References 85 publications

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“…This is because of their inelegant appearance and other changes that potentially affect functions of the formulation (e.g., higher residual water, pH change, slower dissolution, solute crystallization), although the collapse phenomena usually exerts only limited direct damage to the protein structure. 18) The T g ′ (glass transition temperature of maximally freeze-concentrated solute phase) obtained through thermal analysis has often been used as surrogate of the collapse temperature (T c ). 1) Recent advances in freeze-drying microscopy (FDM) analysis have enabled direct observation of the collapse phenomena of frozen solutions in a small reduced-pressure cell that mimic the primary drying process.…”

mentioning

confidence: 99%

Component Crystallization and Physical Collapse during Freeze-Drying of <small>L</small>-Arginine–Citric Acid Mixtures

Yamaki

Ohdate

Nakadai

et al. 2012

CHEMICAL & PHARMACEUTICAL BULLETIN

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Component crystallization and physical collapse during freeze-drying of aqueous solutions containing protein-stabilizing L-arginine and citric acid mixtures were studied. Freeze-drying microscopy (FDM) and thermal analysis of the solute-mixture frozen solutions showed collapse onset at temperatures (T c ) approximately 10°C higher than their T g ′s (glass transition temperatures of the maximally freeze-concentrated solute phase). Experimental freeze-drying of these solutions at a low chamber pressure showed the occurrence of physical collapse at shelf temperatures close to or slightly higher than the T c . Slower ice sublimation at higher chamber pressures induced the physical collapse from lower shelf temperatures. The large effect of chamber pressures on the collapse-inducing shelf temperatures confirmed significance of the sublimation-related heat loss on the sublimation interface temperature during the primary drying. Drying of the single-solute L-arginine solution resulted in cake-structure solids composed of its anhydrous crystal. Thermal and powder X-ray diffraction (PXRD) analysis suggested slow crystal nucleation of L-arginine dihydrate in the frozen solutions. Characterization of the frozen solutions and freeze-dried solids should enable rational formulation design and process control of amino acid-containing lyophilized pharmaceuticals.Key words freeze-drying; crystallization; glass; lyophilization; collapse; thermal analysis Clinical applications of protein pharmaceuticals such as therapeutic antibodies are increasing. However, marginal storage stabilities of many proteins in the aqueous solutions emphasize the importance of developing freeze-dried formulations. Many lyophilized protein formulations contain disaccharides (e.g., sucrose and trehalose) that protect the proteins thermodynamically from structural changes during the freeze-drying process and kinetically from chemical degradation during subsequent storage.1,2) Some basic amino acid (e.g., L-arginine and L-histidine) and multivalent acid (e.g., H 3 PO 4 and citric acid) mixtures are practical alternative stabilizers for protein formulations.3-6) The mixtures protect proteins from conformation-altering dehydration stress during the process. These mixtures form glass-state amorphous solids through networks of hetero-component molecular interactions between the amino and carboxyl groups, and thus improve chemical stability of the dried proteins during storage. 5,7)L-Arginine also increases solubility of various proteins without apparent changes in their conformation. [8][9][10] Freeze-drying is a typical high-energy process, and varying its parameters significantly varies the formulation quality, including the cake appearance, component crystallinity, residual water, and stability of the active pharmaceutical ingredients (APIs).11,12) Failure of a biopharmaceutical lyophilization batch would lead to the loss of the therapeutic protein often more expensive than small molecular APIs. Freezing of aqueous solutions concentrates most solutes to a s...

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mentioning

confidence: 99%

Component Crystallization and Physical Collapse during Freeze-Drying of <small>L</small>-Arginine–Citric Acid Mixtures

Yamaki

Ohdate

Nakadai

et al. 2012

CHEMICAL & PHARMACEUTICAL BULLETIN

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“…Use of OCT-FDM will be a significant advantage when processing formulations that can be freeze-dried above the LT-FDM-determined T c without loss of product quality. There have been numerous reports of successful freeze-drying above the LT-FDM determined collapse temperatures with no evidence of macroscopic collapse of freeze-dried cake [5,[37][38][39][40][41][42][43][44], but these investigations were performed on a trial and error basis with no representative data of T c measurements in a vial to validate the decision to dry at higher temperatures. T c measured by OCT-FDM provides quantitative justification for freeze-drying above the T c as measured by LT-FDM, which is in line with QbD principles.…”

Section: Measurement Resultsmentioning

confidence: 98%

“…A temperature excursion above the critical temperature during drying could lead to a loss of physical structure of the lyophilized material, high residual moisture content, poor reconstitution times, and compromised long-term stability for the pharmaceutical product. For some formulations, in particular, high-concentration protein formulations, it is possible to lyophilize above the critical temperature (as measured using currently available instrumentation) with no impact on long-term stability [4,5].…”

Section: Coupling Of Lyophilization Process and Product Attributes: Lmentioning

confidence: 99%

Advances in Instrumental Analysis Applied to the Development of Lyophilization Cycles

Kessler

Sharma²,

Mujat

2015

Lyophilized Biologics and Vaccines

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The lyophilization process is commonly used to formulate compounds that are unstable in aqueous solution. In order to develop a successful lyophilization process, a comprehensive understanding of the physical and chemical characteristics of formulations in the frozen and freeze-dried form is essential.The three crucial steps in the lyophilization process are: freezing, primary drying, and secondary drying. The freezing process involves transformation of a liquid formulation to a frozen state. During this transformation, the key transition events are ice nucleation, crystallization of water, and simultaneous increase in solute concentration. Once the formulation is frozen, crystalline components crystallize out. Most disaccharides and proteins tend to remain in an amorphous phase and at the end of the freezing step may contain up to ~ 20 % of supercooled water. These transitions during the freezing process can be illustrated using a state diagram of a binary solution of sucrose and water (Fig. 1) [1]. Point A shows the initial temperature and composition of the liquid formulation. As the solution is cooled, ice nuclei form in the solution (point B). This event typically occurs below the thermodynamic equilibrium freezing point of the formulation. Ice nucleation is an exothermic event that leads to an increase in the solution temperature (point C). As the solution is further cooled, the solutes (such as buffer salts) may crystallize out (point D) at the eutectic temperature ( T eu ). For a binary system, W e represents the weight of crystalline solute at T e . If the solutes remain amorphous (example sucrose), a glass transition event is observed (point E) at the glass transition temperature of the maximally freeze-con-

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“…Freeze-drying below T c is necessary to ensure elegant appearance. Collapse may also lead to higher residual water after secondary drying and can also impact stability in some cases by either negatively impacting or improving stability [25,46]. FDM is the most common method used for the measurement of collapse temperature.…”

Section: Liquid Characterizationmentioning

confidence: 99%

“…First, the product temperature limitation for an amorphous system is mainly based on the collapse temperature ( T c ) measured by FDM, and the obtained maximum product temperature may not be the "failure point." It has been reported that collapse may not be detrimental to the in-process or long-term stability of freeze-dried proteins [46,53], and it is possible to perform primary drying at temperatures above the T c for some formulations such as high concentration protein formulations or formulations containing both crystalline and amorphous components [6]. Systems such as these may be dried at much higher temperature, well above the T c , without macroscopic product collapse or loss of any perceptible measure of product quality.…”

Section: Expand the Design Space Using A Scale-down Modelmentioning

confidence: 99%

Lyophilization of Therapeutic Proteins in Vials: Process Scale-Up and Advances in Quality by Design

Wang

McCoy²,

Pikal

et al. 2015

Lyophilized Biologics and Vaccines

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Systematic investigation of the effect of lyophilizate collapse on pharmaceutically relevant proteins I: Stability after freeze‐drying

Cited by 110 publications

References 85 publications

Component Crystallization and Physical Collapse during Freeze-Drying of <small>L</small>-Arginine–Citric Acid Mixtures

Component Crystallization and Physical Collapse during Freeze-Drying of <small>L</small>-Arginine–Citric Acid Mixtures

Advances in Instrumental Analysis Applied to the Development of Lyophilization Cycles

Lyophilization of Therapeutic Proteins in Vials: Process Scale-Up and Advances in Quality by Design

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