Impact of vacuum-induced surface freezing on inter- and intra-vial heterogeneity.

This paper aimed to study the impact of freezing on both within-batch (inter-vial) and within-product (intra-vial) heterogeneity. This analysis has been carried out using two freezing protocols, the conventional shelf-ramped method and the Vacuum Induced Surface Freezing, and placebo formulations containing both crystallizing (mannitol) and amorphous (lactose and sucrose) excipients. The freezing conditions (i.e., the temperature of freezing, the temperature and time of the equilibration phase, and the filling volume) were found to have a dramatic impact on both the within-batch and the within-product homogeneity. Overall, we observed that the control of freezing can effectively minimize the variability in product characteristics, and moisture content, within the same batch. In addition to more uniform production, the control of freezing was found to be fundamental to achieve a more uniform product than that produced by the shelf-ramped freezing method. The influence of the freezing protocol on the crystallization process of mannitol was also investigated, showing that the temperature of freezing plays a key role in the formation of the mannitol polymorphs.

[1]  C Vervaet,et al.  In-line and real-time process monitoring of a freeze drying process using Raman and NIR spectroscopy as complementary process analytical technology (PAT) tools. , 2009, Journal of pharmaceutical sciences.

[2]  Romà Tauler,et al.  Chemometrics applied to unravel multicomponent processes and mixtures: Revisiting latest trends in multivariate resolution , 2003 .

[3]  Michael J. Pikal,et al.  Determination of End Point of Primary Drying in Freeze-Drying Process Control , 2010, AAPS PharmSciTech.

[4]  Geoffrey Lee,et al.  Freeze-drying using vacuum-induced surface freezing. , 2002, Journal of pharmaceutical sciences.

[5]  A. J. Cannon,et al.  The influence of lyophilization on the polymorphic behavior of mannitol. , 2000, PDA journal of pharmaceutical science and technology.

[6]  P. Schmidt,et al.  Investigations on polymorphism of mannitol/ sorbitol mixtures after spray-drying using Differential scanning calorimetry, X-ray diffraction and Near-Infrared spectroscopy , 2000 .

[7]  W. Rau.  Eiskeimbildung durch dielektrische Polarisation , 1951 .

[8]  J. Ketolainen,et al.  Structural attributes of model protein formulations prepared by rapid freeze-drying cycles in a microscale heating stage. , 2014, European journal of pharmaceutics and biopharmaceutics : official journal of Arbeitsgemeinschaft fur Pharmazeutische Verfahrenstechnik e.V.

[9]  Michael J. Pikal,et al.  Heat and mass transfer scale-up issues during freeze drying: II. Control and characterization of the degree of supercooling , 2004, AAPS PharmSciTech.

[10]  R. Suryanarayanan,et al.  Characterization and crystal structure of D-mannitol hemihydrate. , 2004, Journal of pharmaceutical sciences.

[11]  Davide Fissore,et al.  PAT Tools for the Optimization of the Freeze-Drying Process , 2009 .

[12]  D. Mishra,et al.  Existence of a mannitol hydrate during freeze-drying and practical implications. , 1999, Journal of pharmaceutical sciences.

[13]  Davide Fissore,et al.  On the Methods Based on the Pressure Rise Test for Monitoring a Freeze-Drying Process , 2010 .

[14]  J. Carpenter,et al.  The ice nucleation temperature determines the primary drying rate of lyophilization for samples frozen on a temperature-controlled shelf. , 2001, Journal of pharmaceutical sciences.

[15]  Michael J. Pikal,et al.  The secondary drying stage of freeze drying: drying kinetics as a function of temperature and chamber pressure☆ , 1990 .

[16]  R. Pisano,et al.  Vacuum-Induced Nucleation as a Method for Freeze-Drying Cycle Optimization , 2014 .

[17]  Davide Fissore,et al.  Quality by design: optimization of a freeze-drying cycle via design space in case of heterogeneous drying behavior and influence of the freezing protocol , 2013, Pharmaceutical development and technology.

[18]  Kyuya Nakagawa,et al.  Redistribution of Protein Biological Activity in a Freeze-Dried Cake , 2013 .

[19]  J. Rollinger,et al.  Energy/temperature diagram and compression behavior of the polymorphs of D-mannitol. , 2000, Journal of pharmaceutical sciences.

[20]  Sabrina Grassini,et al.  Non-Invasive Temperature Monitoring in Freeze Drying: Control of Freezing as a Case Study , 2015 .

[21]  Akira Yabe,et al.  Active control of phase change from supercooled water to ice by ultrasonic vibration 1. Control of freezing temperature , 2001 .

[22]  I. Trelea,et al.  Effect of controlled ice nucleation on primary drying stage and protein recovery in vials cooled in a modified freeze-dryer. , 2009, Journal of biomechanical engineering.

[23]  S. Sonja Sekulic,et al.  Multivariate data analysis for Raman imaging of a model pharmaceutical tablet , 2005 .

[24]  S. Nail,et al.  The physical state of mannitol after freeze-drying: effects of mannitol concentration, freezing rate, and a noncrystallizing cosolute. , 1998, Journal of pharmaceutical sciences.

[25]  Julien Andrieu,et al.  Influence of controlled nucleation by ultrasounds on ice morphology of frozen formulations for pharmaceutical proteins freeze-drying , 2006 .

[26]  Wenjin Cao,et al.  Differentiation and quantitative determination of surface and hydrate water in lyophilized mannitol using NIR spectroscopy. , 2006, Journal of pharmaceutical sciences.

[27]  Amelia Carolina Sparavigna,et al.  Freeze-drying of enzymes in case of water-binding and non-water-binding substrates. , 2013, European journal of pharmaceutics and biopharmaceutics : official journal of Arbeitsgemeinschaft fur Pharmazeutische Verfahrenstechnik e.V.

[28]  C Vervaet,et al.  Implementation of a process analytical technology system in a freeze-drying process using Raman spectroscopy for in-line process monitoring. , 2007, Analytical chemistry.

[29]  Wolfgang Friess,et al.  The freezing step in lyophilization: physico-chemical fundamentals, freezing methods and consequences on process performance and quality attributes of biopharmaceuticals. , 2011, European journal of pharmaceutics and biopharmaceutics : official journal of Arbeitsgemeinschaft fur Pharmazeutische Verfahrenstechnik e.V.

[30]  Davide Fissore,et al.  In-Line and Off-Line Optimization of Freeze-Drying Cycles for Pharmaceutical Products , 2013 .

[31]  R. Peczalski,et al.  A theoretical model for ice primary nucleation induced by acoustic cavitation. , 2010, Ultrasonics sonochemistry.

[32]  Michael J. Pikal,et al.  Reduced Pressure Ice Fog Technique for Controlled Ice Nucleation during Freeze-Drying , 2009, AAPS PharmSciTech.

[33]  Jinsong Liu,et al.  A Study of the Impact of Freezing on the Lyophilization of a Concentrated Formulation with a High Fill Depth , 2005, Pharmaceutical development and technology.

[34]  R. Suryanarayanan,et al.  Influence of Processing Conditions on the Physical State of Mannitol—Implications in Freeze-Drying , 2007, Pharmaceutical Research.

[35]  Xiaolin Tang,et al.  Freeze-Drying Process Design by Manometric Temperature Measurement: Design of a Smart Freeze-Dryer , 2005, Pharmaceutical Research.

[36]  Davide Fissore,et al.  In-line optimization and control of an industrial freeze-drying process for pharmaceuticals. , 2010, Journal of pharmaceutical sciences.

[37]  Akira Yabe,et al.  Active control of phase change from supercooled water to ice by ultrasonic vibration 2. Generation of ice slurries and effect of bubble nuclei , 2001 .

[38]  George Zografi,et al.  The molecular basis of moisture effects on the physical and chemical stability of drugs in the solid state , 1990 .