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Alternative Methods of Controlling Nucleation in Freeze Drying

  • Roberto PisanoEmail author
Protocol
Part of the Methods in Pharmacology and Toxicology book series (MIPT)

Abstract

The control of freezing, and particularly of the nucleation temperature, is one of the most challenging aspects of the development of a lyophilization cycle. Technological advances of recent years have increased the efficiency with which nucleation temperature can be adjusted. This chapter discusses these technologies, as well as some emerging technologies that might play an important role in near future. In particular each technology is presented in terms of easy to be implemented, scalability on industrial units, influence on product morphology, protein preservation, intra-vial and vial-to-vial heterogeneity, and process performance.

Key words

Control Freezing Nucleation 

Abbreviations

HES

Hydroxyethyl starch

SSA

Specific surface area

VISF

Vacuum-induced surface freezing

Symbols

Dp

Pore size, m

Jw

Vapour flux, kg m−2 s−1

Mw

Molecular weight of water, kg mol−1

Pice

Vapour pressure of ice, Pa

Pw

Partial pressure of water inside the drying chamber, Pa

Rp

Resistance to mass transfer, m s−1

R

Ideal gas constant, J mol−1 K−1

Tg

Glass transition temperature, K

Teu

Eutectic temperature, K

Tn

Nucleation temperature, K

Greek Letters

ε

Porosity of the lyophilized product, –

τ

Tortuosity of the lyophilized product, –

References

  1. 1.
    Myerson AS (ed) (2002) Handbook of industrial crystallization. Butterworth Heinemann, Boston, MAGoogle Scholar
  2. 2.
    Blond G (1988) Velocity of linear crystallization of ice in macromolecular systems. Cryobiology 25(1):61–66PubMedCrossRefPubMedCentralGoogle Scholar
  3. 3.
    Wilson PW, Heneghan AF, Haymet ADJ (2003) Ice nucleation in nature: supercooling point (SCP) measurements and the role of heterogeneous nucleation. Cryobiology 46(1):88–98PubMedCrossRefPubMedCentralGoogle Scholar
  4. 4.
    Matsumoto M, Saito S, Ohmine I (2002) Molecular dynamics simulation of the ice nucleation and growth process leading to water freezing. Nature 416(6879):409–413PubMedCrossRefPubMedCentralGoogle Scholar
  5. 5.
    Mason BJ (1958) The supercooling and nucleation of water. Adv Phys 7(26):221–234CrossRefGoogle Scholar
  6. 6.
    Volmer M (1939) Kinetic der Phasenbildung. Steinkoff, DresdenGoogle Scholar
  7. 7.
    Lide DR (2008) CRC handbook of chemistry and physics, 88th edn. CRC Press Taylor & Francis, New York, NY, pp 6–8Google Scholar
  8. 8.
    Searles JA, Carpenter JF, Randolph TW (2001) The ice nucleation temperature determines the primary drying rate of lyophilization for samples frozen on a temperature-controlled shelf. J Pharm Sci 90(7):860–871PubMedPubMedCentralCrossRefGoogle Scholar
  9. 9.
    Pisano R, Fissore D, Barresi AA, Brayard P, Chouvenc P, Woinet B (2013) Quality by design: optimization of a freeze-drying cycle via design space in case of heterogeneous drying behavior and influence of the freezing protocol. Pharm Dev Technol 18:1–16CrossRefGoogle Scholar
  10. 10.
    Tang XC, Pikal MJ (2004) Design of freeze-drying processes for pharmaceuticals: practical advice. Pharm Res 21:191–200CrossRefGoogle Scholar
  11. 11.
    Hsu CC, Nguyen HM, Yeung DA, Brooks DA, Koe GS, Bewley TA, Pearlman R (1995) Surface denaturation at solid-void interface--a possible pathway by which opalescent particulates form during the storage of lyophilized tissue-type plasminogen activator at high temperatures. Pharm Res 12(1):69–77PubMedCrossRefGoogle Scholar
  12. 12.
    Heller MC, Carpenter JF, Randolph TW (1999) Application of a thermodynamic model to the prediction of phase separations in freeze-concentrated formulations for protein lyophilization. Arch Biochem Biophys 363(2):191–201PubMedCrossRefGoogle Scholar
  13. 13.
    Heller MC, Carpenter JF, Randolph T (1999) Protein formulation and lyophilization cycle design: prevention of damage due to freeze-concentration induced phase separation. Biotechnol Bioeng 63(2):166–174PubMedCrossRefGoogle Scholar
  14. 14.
    Liu J, Viverette T, Virgin M, Anderson M, Dalal P (2005) A study of the impact of freezing on the lyophilization of a concentrated formulation with a high fill depth. Pharm Dev Technol 10(2):261–272PubMedCrossRefGoogle Scholar
  15. 15.
    Snell GD, Cloudman AM (1943) The effect of rate of freezing on the survival of fourteen transplantable tumors of mice. Cancer Res 3(6):396–400Google Scholar
  16. 16.
    Talstad I, Dalen H, Scheie P, Røli J (1981) Patterns in quench-frozen, freeze-dried, blood proteins. Scan Electron Microsc (Pt 2):319–326Google Scholar
  17. 17.
    Scheie P, Dalen H, Saetersdal T, Myklebust R (1982) Freezing patterns in quench frozen, freeze-dried polyvinylpyrrolidone (PVP). J Microsc 126(3):237–242CrossRefGoogle Scholar
  18. 18.
    Patapoff TW, Overcashier DE (2002) The importance of freezing on lyophilization cycle development. Biopharm 15(1):16–21Google Scholar
  19. 19.
    Hottot A, Vessot S, Andrieu J (2007) Freeze drying of pharmaceuticals in vials: influence of freezing protocol and sample configuration on ice morphology and freeze-dried cake texture. Chem Eng Process 46(7):666–674CrossRefGoogle Scholar
  20. 20.
    Jiang S, Nail SL (1998) Effect of process conditions on recovery of protein activity after freezing and freeze-drying. Eu J Pharm Biopharm 45(3):249–257CrossRefGoogle Scholar
  21. 21.
    Zhou Y, Gasteyer TH, Grinter NJ, Cheng AT, Ho S Y-C, Sever RR (2014) Method and system for nucleation control in a controlled rate freezer (CRF). Patent US 8,794,013 B2, 5 Aug 2014Google Scholar
  22. 22.
    Searles JA (2004) Freezing and annealing phenomena in lyophilization. In: Rey L, May JC (eds) Freeze-drying/lyophilization of pharmaceutical and biological products, 2nd edn. Marcel Dekker, New York, NY, pp 109–145Google Scholar
  23. 23.
    Lifshitz IM, Slyozov VV (1961) The kinetics of precipitation from supersaturated solid solutions. J Phys Chem Solid 19(1-2):35–50CrossRefGoogle Scholar
  24. 24.
    Gatlin L, Deluca PP (1980) A study of the phase transitions in frozen antibiotic solutions by differential scanning calorimetry. J Parenter Drug Assoc 34(5):398–408PubMedPubMedCentralGoogle Scholar
  25. 25.
    Carpenter JF, Pikal MJ, Chang BS, Randolph TW (1997) Rational design of stable lyophilized protein formulations: some practical advice. Pharm Res 14(8):969–975CrossRefGoogle Scholar
  26. 26.
    Simatos D, Faure M, Bonjour E, Couach M (1975) The physical state of water at low temperatures in plasma with different water contents as studied by differential thermal analysis and differential scanning calorimetry. Cryobiology 12(3):202–208PubMedCrossRefGoogle Scholar
  27. 27.
    Sahagian ME, Goff HD (1994) Effect of freezing rate on the thermal, mechanical and physical aging properties of the glassy state in frozen sucrose solutions. Thermochim Acta 246(2):271–283CrossRefGoogle Scholar
  28. 28.
    Lu X, Pikal MJ (2004) Freeze‐drying of mannitol–trehalose–sodium chloride‐based formulations: the impact of annealing on dry layer resistance to mass transfer and cake structure. Pharm Dev Technol 9(1):85–95CrossRefGoogle Scholar
  29. 29.
    Gatlin LA, Nail SL (1994) Freeze drying: a practical overview. In: Harrison R (ed) Protein purification process engineering, 1st edn. Marcel Dekker, New York, NY, pp 317–367Google Scholar
  30. 30.
    Franks F (1998) Freeze-drying of bioproducts: putting principles into practice. Eu J Pharm Biopharm 45(3):221–229CrossRefGoogle Scholar
  31. 31.
    Esfandiary R, Gattu SK, Stewart JM, Patel SM (2016) Effect of freezing on lyophilization process performance and drug product cake appearance. J Pharm Sci 105(4):1427–1433PubMedCrossRefPubMedCentralGoogle Scholar
  32. 32.
    Searles JA, Carpenter JF, Randolph TW (2001) Annealing to optimize the primary drying rate, reduce freezing-induced drying rate heterogeneity, and determine Tg’ in pharmaceutical lyophilization. J Pharm Sci 90(7):872–887PubMedCrossRefPubMedCentralGoogle Scholar
  33. 33.
    Layton RG (1973) Ice nucleation by silver iodide: influence of an electric field. J Colloid Interface Sci 42(1):214–217CrossRefGoogle Scholar
  34. 34.
    Margaritis A, Bassi AS (1991) Principles and biotechnological applications of bacterial ice nucleation. Crit Rev Biotechnol 11(3):277–295PubMedCrossRefPubMedCentralGoogle Scholar
  35. 35.
    Lindong W, Shannon NT, Anisa S, Shannon LS, Mehmet T (2017) Controlled ice nucleation using freeze-dried Pseudomonas syringae encapsulated in alginate beads. Cryobiology 75(4):1–6Google Scholar
  36. 36.
    Cochet N, Widehem P (2000) Ice crystallization by Pseudomonas syringae. Appl Microbiol Biotechnol 54(2):153–161PubMedCrossRefPubMedCentralGoogle Scholar
  37. 37.
    Rau W (1951) Eiskeimbildung durch dielektrische Polarisation. Zeitschrift für Naturforschung A 6(11):649–657Google Scholar
  38. 38.
    Shichiri T, Araki Y (1986) Nucleation mechanism of ice crystals under electrical effect. J Cryst Growth 78(3):502–508CrossRefGoogle Scholar
  39. 39.
    Wei S, Zhong C, Su-Yi H (2005) Molecular dynamics simulation of liquid water under the influence of an external electric field. Mol Simulat 31(8):555–559CrossRefGoogle Scholar
  40. 40.
    Hozumi T, Saito A, Okawa S, Eshita Y (2003) Effects of shapes of electrodes on freezing of supercooled water in electric freeze control. Int J Refrig 26(5):537–542CrossRefGoogle Scholar
  41. 41.
    Petersen A, Schneider H, Rau G, Glasmacher B (2006) A new approach for freezing of aqueous solutions under active control of the nucleation temperature. Cryobiology 53(2):248–257PubMedPubMedCentralCrossRefGoogle Scholar
  42. 42.
    Petersen A, Rau G, Glasmacher B (2006) Reduction of primary freeze-drying time by electric field induced ice nucleus formation. Heat Mass Transfer 42(10):929–938CrossRefGoogle Scholar
  43. 43.
    Kuu W-Y, Doty MJ, Rebbeck CL, Hurst WS, Cho YK (2013) Gap-freezing approach for shortening the lyophilization cycle time of pharmaceutical formulations-demonstration of the concept. J Pharm Sci 102(8):2572–2588PubMedCrossRefGoogle Scholar
  44. 44.
    Kuu W-Y, Doty MJ, Hurst WS, Rebbeck CL (2017) Optimization of nucleation and crystallization for lyophilization using gap freezing. Patent US 9,625,210 B2, 18 Apr 2017Google Scholar
  45. 45.
    Capozzi LC, Pisano R (2016) Freeze-drying of suspended vials: the first step toward continuous manufacturing. In: Proceedings of the 2nd international symposium on continuous manufacturing of pharmaceuticals, Cambridge, 26–27 September 2016Google Scholar
  46. 46.
    Rowe TD (1992) A technique for the nucleation of ice. In: Brown F, May JC (eds) Proceedings of international symposium on biological product freeze-drying and formulation, Bethesda, 24-26 October 1990. Developments in biological standardization, vol 74. Karger, New York, NY, p 377Google Scholar
  47. 47.
    Mason BJ, Ludlam FH (1951) The microphysics of clouds. Rep Prog Phys 14(1):147–195CrossRefGoogle Scholar
  48. 48.
    Rambhatla S, Ramot R, Bhugra C, Pikal MJ (2004) Heat and mass transfer scale-up issues during freeze drying: II. Control and characterization of the degree of supercooling. AAPS PharmSciTech 5(4):54–62CrossRefGoogle Scholar
  49. 49.
    Patel SM, Bhugra C, Pikal MJ (2009) Reduced pressure ice fog technique for controlled ice nucleation during freeze-drying. AAPS PharmSciTech 10(4):1406–1411PubMedPubMedCentralCrossRefGoogle Scholar
  50. 50.
    Demarco F, Renzi E, Lee R, Chakravarty P (2012) Ice fog as a means to induce uniform ice nucleation during lyophilization. Biopharm Int 25(1):33–38Google Scholar
  51. 51.
    Weija L (2012) Controlled nucleation during freezing step of freeze drying cycle using pressure differential ice fog distribution. Patent US 8,839,528 B2, 23 Sept 2014Google Scholar
  52. 52.
    Geidobler R, Mannschedel S, Winter G (2012) A new approach to achieve controlled ice nucleation of supercooled solutions during the freezing step in freeze-drying. J Pharm Sci 101(12):4409–4413PubMedCrossRefGoogle Scholar
  53. 53.
    Hickling R (1965) Nucleation of freezing by cavity collapse and its relation to cavitation damage. Nature 206(4987):915–917CrossRefGoogle Scholar
  54. 54.
    Li B, Sun D-W (2002) Novel methods for rapid freezing and thawing of foods – a review. J Food Eng 54(3):175–182CrossRefGoogle Scholar
  55. 55.
    Petzold G, Aguilera JM (2009) Ice morphology: fundamentals and technological applications in foods. Food Biophys 4(4):378–396CrossRefGoogle Scholar
  56. 56.
    Inada T, Zhang X, Yabe A, Kozawa Y (2001) Active control of phase change from supercooled water to ice by ultrasonic vibration 1. Control of freezing temperature. J Heat Mass Transfer 44(23):4523–4531CrossRefGoogle Scholar
  57. 57.
    Zhang X, Inada T, Yabe A, Lu S, Kozawa Y (2001) Active control of phase change from supercooled water to ice by ultrasonic vibration 2. Generation of ice slurries and effect of bubble nuclei. J Heat Mass Transfer 44(23):4533–4539CrossRefGoogle Scholar
  58. 58.
    Hunt JD, Jackson KA (1966) Nucleation of solid in an undercooled liquid by cavitation. J Appl Phys 17(1):254–257CrossRefGoogle Scholar
  59. 59.
    Zhang X, Inada T, Tezuka A (2003) Ultrasonic-induced nucleation of ice in water containing air bubbles. Ultrason Sonochem 10(2):71–76PubMedCrossRefGoogle Scholar
  60. 60.
    Nakagawa K, Hottot A, Vessot S, Andrieu J (2006) Influence of controlled nucleation by ultrasounds on ice morphology of frozen formulations for pharmaceutical proteins freeze-drying. Chem Eng Process 45(9):783–791CrossRefGoogle Scholar
  61. 61.
    Hottot A, Nakagawa K, Andrieu J (2008) Effect of ultrasound-controlled nucleation on structural and morphological properties of freeze-dried mannitol solutions. Chem Eng Res Des 86(2):193–200CrossRefGoogle Scholar
  62. 62.
    Saclier M, Peczalski R, Andrieu J (2010) Effect of ultrasonically induced nucleation on ice crystal size and shape during freezing in vials. Chem Eng Sci 65(10):3064–3071CrossRefGoogle Scholar
  63. 63.
    Acton E, Morris GJ (2004) Method and apparatus for freeze drying material. Patent Application GB 2,400,901 A, 27 Oct 2004Google Scholar
  64. 64.
    Passot S, Tréléa IC, Marin M, Galan M, Morris GJ, Fonseca F (2009) Effect of controlled ice nucleation on primary drying stage and protein recovery in vials cooled in a modified freeze-dryer. J Biochem Eng 131(7):074511Google Scholar
  65. 65.
    Kanda Y, Aoki M, Kosugi T (1992) Freezing of tofu by pressure shift freezing and its structure. Nippon Shokuhin Kogyo Gakkaishai 39(7):608–614CrossRefGoogle Scholar
  66. 66.
    Martino MN, Otero L, Sanz PD, Zaritzky NE (1998) Size and location of ice crystals in pork frozen by high-pressure-assisted freezing as compared to classical methods. Meat Sci 50(3):303–313PubMedCrossRefGoogle Scholar
  67. 67.
    Sanz PD, Otero L, de Elvira C, Carrasco JA (1997) Freezing processes in high-pressure domains. Int J Refrig 20(5):301–307CrossRefGoogle Scholar
  68. 68.
    Knorr D, Schlueter O, Heinz V (1998) Impact of high hydrostatic pressure on phase transitions of foods. Food Technol 52(9):42–45Google Scholar
  69. 69.
    Otero L, Sanz PD (1998) High-pressure shift freezing. Part 1. Amount of ice instantaneously formed in the process. Biotechnol Prog 16(6):1030–1036CrossRefGoogle Scholar
  70. 70.
    Fernández PP, Otero L, Guignon B, Sanz PD (2006) High-pressure shift freezing versus high-pressure assisted freezing: effects on the microstructure of a food model. Food Hydrocoll 20(4):510–522CrossRefGoogle Scholar
  71. 71.
    Gasteyer TH, Sever RR, Hunek B, Grinter N, Verdone ML (2017) Lyophilization system and method. Patent US 9,651,305 B2, 16 May 2017Google Scholar
  72. 72.
    Gasteyer TH III, Sever RR, Hunek B, Grinter N, Verdone ML (2015) Method of inducing nucleation of a material. Patent US 9,453,675 B2, 25 Sept 2016, Patent EP 1,982,133 B1, 15 Jul 2015Google Scholar
  73. 73.
    Konstantinidis AK, Kuu W, Otten L, Nail SL, Sever RR, Bons V, Debo D, Pikal MJ (2011) Controlled nucleation in freeze‐drying: effects on pore size in the dried product layer, mass transfer resistance, and primary drying rate. J Pharm Sci 100(8):3453–3470CrossRefPubMedPubMedCentralGoogle Scholar
  74. 74.
    Geidobler R, Winter G (2013) Controlled ice nucleation in the field of freeze-drying: fundamentals and technology review. Eu J Pharm Biopharm 85(2):214–222CrossRefGoogle Scholar
  75. 75.
    McDonald K, Sun D-W (2000) Vacuum cooling technology for the food processing industry: a review. J Food Eng 45(2):55–65CrossRefGoogle Scholar
  76. 76.
    Kramer M, Sennhenn B, Lee G (2002) Freeze-drying using vacuum-induced surface freezing. J Pharm Sci 91:433–443PubMedCrossRefPubMedCentralGoogle Scholar
  77. 77.
    Oddone I, Pisano R, Bullich R, Stewart P (2014) Vacuum-induced nucleation as a method for freeze-drying cycle optimization. Ind Eng Chem Res 53:18236–18244CrossRefGoogle Scholar
  78. 78.
    Roy ML, Pikal MJ (1989) Process control in freeze drying: determination of the end point of sublimation drying by an electronic moisture sensor. J Parenter Sci Technol 43(2):60–66PubMedPubMedCentralGoogle Scholar
  79. 79.
    Pisano R, Capozzi LC (2017) Prediction of product morphology of lyophilized drugs in the case of Vacuum Induced Surface Freezing. Chem Eng Res Des 125(1):119–129CrossRefGoogle Scholar
  80. 80.
    Oddone I, Van Bockstal P-J, De Beer T, Pisano R (2016) Impact of vacuum-induced surface freezing on inter- and intra-vial heterogeneity. Eu J Pharm Biopharm 103(1):167–178CrossRefGoogle Scholar
  81. 81.
    Oddone I, Fulginiti D, Barresi AA, Grassini S, Pisano R (2015) Non-invasive temperature monitoring in freeze drying: control of freezing as a case study. Drying Technol 33(13):1621–1630CrossRefGoogle Scholar
  82. 82.
    Kim AI, Akers MJ, Nail SL (1998) The physical state of mannitol after freeze-drying: effects of mannitol concentration, freezing rate, and a noncrystallizing cosolute. J Pharm Sci 87(8):931–935PubMedCrossRefGoogle Scholar
  83. 83.
    Cavatur RK, Vemuri NM, Pyne A, Chrzan Z, Toledo-Velasquez D, Suryanarayanan R (2002) Crystallization behavior of mannitol in frozen aqueous solutions. Pharm Res 19(6):894–900PubMedCrossRefGoogle Scholar
  84. 84.
    Izutsu K, Yoshioka S, Kojima S (1994) Physical stability and protein stability of freeze-dried cakes during storage at elevated temperatures. Pharm Res 45(1):5–8Google Scholar
  85. 85.
    Liao X, Krishnamurthy R, Suryanarayanan R (2007) Influence of processing conditions on the physical state of mannitol - implications in freeze-drying. Pharm Res 24(2):370–376PubMedCrossRefGoogle Scholar
  86. 86.
    Barresi AA, Ghio S, Fissore D, Pisano R (2009) Freeze drying of pharmaceutical excipients close to collapse temperature: influence of the process conditions on process time and product quality. Drying Technol 27(6):805–816CrossRefGoogle Scholar
  87. 87.
    Webb SD, Cleland JL, Carpenter JF, Randolph TW (2003) Effects of annealing lyophilized and spray-lyophilized formulations of recombinant human interferon-γ. J Pharm Sci 92(4):715–729PubMedCrossRefGoogle Scholar
  88. 88.
    Kasper JC, Friess W (2011) The freezing step in lyophilization: physico-chemical fundamentals, freezing methods and consequences on process performance and quality attributes of biopharmaceuticals. Eu J Pharm Biopharm 78(2):248–263CrossRefGoogle Scholar
  89. 89.
    Kuu WY, O’Bryan KR, Hardwick LM, Paul TW (2011) Product mass transfer resistance directly determined during freeze-drying cycle runs using tunable diode laser absorption spectroscopy (TDLAS) and pore diffusion model. Pharm Dev Technol 16(4):343–357PubMedCrossRefGoogle Scholar
  90. 90.
    Pisano R, Barresi AA, Capozzi LC, Novajra G, Oddone I, Vitale-Brovarone C (2017) Characterization of the mass transfer of lyophilized products based on X-ray micro-computed tomography images. Drying Technol 35(8):933–938CrossRefGoogle Scholar
  91. 91.
    Velardi SA, Barresi A (2008) Development of simplified models for the freeze-drying process and investigation of the optimal operating conditions. Chem Eng Res Des 86(1A):9–22CrossRefGoogle Scholar
  92. 92.
    Franks F, Auffret T (eds) (2007) Freeze-drying of pharmaceuticals and biopharmaceuticals. RSC Publishing, CambridgeGoogle Scholar
  93. 93.
    Pisano R, Fissore D, Barresi AA (2011) Freeze-drying cycle optimization using model predictive control techniques. Ind Eng Chem Res 50(12):7363–7379CrossRefGoogle Scholar
  94. 94.
    Hottot A, Vessot S, Andrieu J (2004) A direct characterization method of the ice morphology. Relationship between mean crystalsize and primary drying times of freeze-drying processes. Drying Technol 22(8):2009–2021CrossRefGoogle Scholar
  95. 95.
    Bursac R, Sever R, Hunek B (2009) A practical method for resolving the nucleation problem in lyophilization. Bioprocess Int:66–72Google Scholar
  96. 96.
    Pikal MJ (1999) Heat and mass transfer in low pressure gases: applications to freeze drying. In: Amidon G, Lee P, Topp L (eds) Transport process in pharmaceutical systems, 1st edn. Marcel Dekker, New York, NY, pp 611–686Google Scholar
  97. 97.
    Pikal MJ, Shah S, Roy ML, Putman R (1990) The secondary drying stage of freeze drying: drying kinetics as a function of temperature and chamber. Int J Pharm 60(3):203–217CrossRefGoogle Scholar
  98. 98.
    Pisano R, Fissore D, Barresi AA (2012) Quality by design in the secondary drying step of a freeze-drying process. Drying Technol 30(11-12):1307–1316CrossRefGoogle Scholar
  99. 99.
    Fissore D, Pisano R, Barresi AA (2011) Monitoring of the secondary drying in freeze-drying of pharmaceuticals. J Pharm Sci 100(2):732–742PubMedCrossRefGoogle Scholar
  100. 100.
    Oddone I, Pisano R, Barresi AA (2017) Influence of controlled ice nucleation on the freeze-drying of pharmaceutical products: the secondary drying step. Int J Pharm 524(1-2):134–140PubMedCrossRefGoogle Scholar
  101. 101.
    Tang X, Nail SL, Pikal MJ (2005) Freeze-drying process design by manometric temperature measurement: design of a smart freeze-dryer. Pharm Res 22(4):685–700PubMedPubMedCentralCrossRefGoogle Scholar
  102. 102.
    Patel SM, Doen T, Pikal MJ (2010) Determination of end point of primary drying in freeze-drying process control. AAPS PharSciTech 11(1):73–84CrossRefGoogle Scholar
  103. 103.
    Strambini GB, Gabellieri E (1996) Proteins in frozen solutions: evidence of ice-induced partial unfolding. Biophys J 70(2I):971–976PubMedPubMedCentralCrossRefGoogle Scholar
  104. 104.
    Wang W (2000) Lyophilization and development of solid protein pharmaceuticals. Int J Pharm 203(1):1–60CrossRefGoogle Scholar
  105. 105.
    Chang BS, Kendrick BS, Carpenter JF (1996) Surface-induced denaturation of proteins during freezing and its inhibition by surfactants. J Pharm Sci 85(12):1325–1330PubMedPubMedCentralCrossRefGoogle Scholar
  106. 106.
    Eckhardt BM, Oeswein JQ, Bewley TA (1991) Effect of freezing on aggregation of human growth hormone. Pharm Res 8(11):1360–1363PubMedCrossRefGoogle Scholar
  107. 107.
    Sarciaux JM, Mansour S, Hageman MJ, Nail SL (1999) Effects of buffer composition and processing conditions on aggregation of bovine IgG during freeze-drying. J Pharm Sci 88(12):1354–1361PubMedCrossRefGoogle Scholar
  108. 108.
    Siew A (2013) Controlling ice nucleation during the freezing step of lyophilization. Pharm Technol 37(5):36–40Google Scholar
  109. 109.
    Umbach M (2017) Freeze drying plant. Patent EP 3,093,597 B1, 27 Dec 2017Google Scholar
  110. 110.
    Ling W (2014) Controlled nucleation during freezing step of freeze drying cycle using pressure differential ice crystals distribution from condensed frost. Patent US 8,875,413 B2, 4 November 2014Google Scholar
  111. 111.
    GEA. Inducing nucleation in industrial freeze dryers. Manufacturing Chemist 2017 (22 Nov). Available at https://www.manufacturingchemist.com/news/article_page/Inducing_nucleation_in_industrial_freeze_dryers/136511
  112. 112.
    Brower J, Lee R, Wexler E, Finley S, Caldwell M, Studer P (2015) New developments in controlled nucleation: commercializing VERISEQ® nucleation technology. In: Varshney D, Singh M (eds) Lyophilized biologics and vaccines. Springer, New York, NY, pp 73–90CrossRefGoogle Scholar
  113. 113.
    Chakravarty P, Lee RC (2013) Method for freeze drying. Patent US 8,549,768 B2, 8 Oct 2013Google Scholar
  114. 114.
    Lee RC, Chakravarty P (2013) Freeze drying method. Patent EP 2,478,313 B1, 25 Oct 2013Google Scholar
  115. 115.
    Azzarella J, Mudhivarthi VK, Wexler E, Ganguly A (2017) Increasing vial to vial homogeneity: an analysis of VERISEQ® nucleation on production scale freeze dryers. BioPharm Int 29(12):36–41Google Scholar
  116. 116.
    Rampersad BM, Sever RR, Humek B, Gasteyer TH III (2012) Freeze-dryer and method of controlling the same. Patent US 8,240,065 B2, 14 Aug 2012Google Scholar
  117. 117.
    Awotwe-Otoo D, Agarabi C, Read EK, Lute S, Brorson KA, Khan MA, Shah RB (2013) Impact of controlled ice nucleation on process performance and quality attributes of a lyophilized monoclonal antibody. Int J Pharm 450(1-2):70–78PubMedPubMedCentralCrossRefGoogle Scholar
  118. 118.
    Sennhenn B, Kramer M (2004) Lyophilization method. Patent US 6,684,524 B1, 3 Feb 2004Google Scholar
  119. 119.
    Arsiccio A, Barresi A, De Beer T, Oddone I, Van Bockstal P-J, Pisano R (2018) Vacuum Induced Surface Freezing as an effective method for improved inter- and intra-vial product homogeneity. Eu J Pharm Biopharm 128(1):210–219CrossRefGoogle Scholar
  120. 120.
    Wexler E, Brower J (2015) New developments in controlled nucleation. Pharm Manufactur 2015:26–29 https://www.pharmamanufacturing.com/articles/2015/new-developments-in-controlled-nucleation/Google Scholar

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Authors and Affiliations

  1. 1.Department of Applied Science and Technology, Molecular Engineering LaboratoryPoliteccnico di TorinoTorinoItaly

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