Optical coherence tomography-based freeze-drying microscopy

Mujat, Mircea; Greco, Kristyn; Galbally-Kinney, Kristin L.; Hammer, Daniel X.; Ferguson, R. Daniel; Iftimia, Nicusor; Mulhall, Phillip A.; Sharma, Puneet; Pikal, Michael J.; Kessler, William J.

doi:10.1364/boe.3.000055

Cited by 27 publications

(17 citation statements)

References 35 publications

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“…Apart from accurately measuring the collapse temperature of the formulation, it also allows the observation of other features of the lyophilization process such as the ice nucleation and freezing process. This technology is more efficient and has a higher resolution and accuracy than the light transmission freeze-dry microscopy (LT-FDM) and differential scanning calorimetry (DSC) tools that were originally used [24]. The results of such measurement of the T g ′ or T eu determine the allowable upper range for the product temperature at the sublimation interface during the lyophilization cycle and such information is expected to be included in a biologics license application (BLA) or new drug application (NDA) by the FDA.…”

Section: Pat Tools For Characterization Of the Bulk Solutionmentioning

confidence: 99%

Lyophilization of Biologics: An FDA Perspective

Awotwe-Otoo

Khan

2015

Lyophilized Biologics and Vaccines

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Section: Pat Tools For Characterization Of the Bulk Solutionmentioning

confidence: 99%

Lyophilization of Biologics: An FDA Perspective

Awotwe-Otoo

Khan

2015

Lyophilized Biologics and Vaccines

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“…Optical coherence tomography-based FDM (OCT-FDM) has been developed as an alternative to LT-FDM that has the advantage of accurate estimation of collapse temperature of a formulation [11,12]. The advantage lies in the 3D OCT-FDM measurement approach wherein the collapse temperature of the formulation is estimated in a vial during the freeze-drying process rather than in a thin film.…”

Section: Coupling Of Lyophilization Process and Product Attributes: Lmentioning

confidence: 99%

“…Recently, a new collapse temperature determination approach was demonstrated based upon the application of OCT interrogation of a product formulation contained within a standard 10-ml pharmaceutical vial undergoing drying in a single-vial freeze-dryer [11,12]. OCT is the optical analog of ultrasound [32,33] providing cross-sectional imaging enabled by the measurement of the magnitude and echo time delay of backscattered light using a Michelson interferometer.…”

Section: Optical Coherence Tomography-based Fdmmentioning

confidence: 99%

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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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“…Other techniques, including near-infrared (NIR) spectroscopy, Raman spectroscopy and optical tomography (14)(15)(16) are also used to study the freezing profile. Challenges associated with these technologies include (1) the placement of a thermocouple probe within the vial will inevitably impact/perturb the processes of ice formation and (2) bulky technologies, such as NIR and Raman probes, which require close placement to the vial in question, do not permit the usual hexagonal arrangement of vials on the freeze drier shelf and therefore provide limited access to those vial in the centre of the cluster.…”

Section: Introductionmentioning

confidence: 99%

Factors Affecting the Use of Impedance Spectroscopy in the Characterisation of the Freezing Stage of the Lyophilisation Process: the Impact of Liquid Fill Height in Relation to Electrode Geometry

et al. 2013

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Abstract. This study aims to investigate the application of impedance spectroscopy using fixed electrode geometries on a standard glass vial in the characterisation of the freezing process of solutions at different fill liquid volumes. Impedance spectra (between 10 and 10 6 Hz) were recorded every 3 min, during the freezing cycle on a solution of 30 mg/mL sucrose contained within 10 mL glass vials having an electrode system (two thin copper foils: w, 18 mm; h, 5 mm) affixed to the external surface of the vial. A fill factor (Φ) was defined in terms of the relative height of the solution volume to the height of the electrodes from the base of the vial. Solution volumes of 1.5 to 5 mL (corresponding to Φ=0.5-1.6) were investigated to establish the applicability of having a fixed electrode geometry for a range of solution volumes. A linear relationship between the time duration of the ice formation/solidification phase and the fill factor suggests that fixed electrode geometries may be used to investigate a range of fill volumes. The benefit of this approach is that it does not invade the solution and hence records the freezing process without providing additional nucleation sites and in a manner which is representative of the entire fill volume.

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Optical coherence tomography-based freeze-drying microscopy

Cited by 27 publications

References 35 publications

Lyophilization of Biologics: An FDA Perspective

Lyophilization of Biologics: An FDA Perspective

Advances in Instrumental Analysis Applied to the Development of Lyophilization Cycles

Factors Affecting the Use of Impedance Spectroscopy in the Characterisation of the Freezing Stage of the Lyophilisation Process: the Impact of Liquid Fill Height in Relation to Electrode Geometry

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