Skip to main content
SpringerLink
Log in

Process Understanding in Freeze-Drying Cycle Development: Applications for Through-Vial Impedance Spectroscopy (TVIS) in Mini-pilot Studies

  • Original Article
  • Published:
Journal of Pharmaceutical Innovation Aims and scope Submit manuscript

Abstract

Purpose

The freeze-drying cycle comprises three stages: (1) freezing, to form ice and to crystallise out any solutes with a propensity to crystallise, (2) primary drying to remove the ice phase by sublimation and (3) secondary drying to remove the remaining unfrozen water which is bound to the remaining matrix of crystalline and amorphous solids. Given the impact of scale on the process outcomes, any freeze-drying cycle developed based on mini-pilot studies will inevitably require measurement technologies for characterising each stage of the cycle at each scale of the process. However, there are inherent challenges in the development of reliable mini-piloting studies, with the first being the fact that no single PAT technology for freeze drying may be implemented across all levels of scale, and the second being the inherent changes in process characteristics (process parameters that result from scale-up).

Methods

Here, we present a new approach for process understanding in freeze-drying cycle development, which uses a through-vial impedance measurement.

Results

The technique has been used to characterise a broad range of features of the process, including, ice onset times, the completion of ice solidification, the glass transition and the structural relaxation of the amorphous solid, a surrogate for primary drying rate and the primary drying end point.

Conclusions

The on-going development of this technology may see the application with microtitre plate technologies for formulation screening (microscale down) and for scale-up into production by using a non-contact probes for monitoring problematic regions within the dryer.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8
Fig. 9
Fig. 10
Fig. 11
Fig. 12

Similar content being viewed by others

Notes

  1. These are not used in production of any commercial product.

  2. These are the vials that are currently available for most commercial products.

References

  1. Tang X, Pikal M. Design of freeze-drying processes for pharmaceuticals: practical advice. Pharm Res. 2004;21(2):191–200. doi:10.1023/b:pham.0000016234.73023.75.

    Article  CAS  PubMed  Google Scholar 

  2. Brulls M, Rasmuson A. Heat transfer in vial lyophilization. Int J Pharm. 2002;246:1–16.

    Article  CAS  PubMed  Google Scholar 

  3. Guttzeit M. Designing an effective PAT-driven scale-up of lyophilization processes. PharmTechnol. 2010;22(11):8.

    Google Scholar 

  4. Grant Y, Dalby PA, Matejtschuk P. Use of design of experiment and microscale down strategies in formulation and cycle development for lyophilization. Am Pharm Rev. 2012;11

  5. Schwegman JJ, Hardwick LM, Akers MJ. Practical formulation and process development of freeze-dried products. Pharm Dev Technol. 2005;10(2):151–73. doi:10.1081/PDT-56308.

    Article  CAS  PubMed  Google Scholar 

  6. Kim AI, Akers MJ, Nail SL. The physical state of mannitol after freeze-drying: effects of mannitol concentration, freezing rate, and a noncrystallizing cosolute. J Pharm Sci. 1998;87(8):931–5. doi:10.1021/js980001d.

    Article  CAS  PubMed  Google Scholar 

  7. Kochs M, Körber C, Heschel I, Nunner B. The influence of the freezing process on vapour transport during sublimation in vacuum-freeze-drying of macroscopic samples. Int J Heat Mass Transf. 1993;36(7):1727–38. doi:10.1016/S0017-9310(05)80159-0.

    Article  CAS  Google Scholar 

  8. Rambhatla S, Tchessalov S, Pikal M. Heat and mass transfer scale-up issues during freeze-drying, III: control and characterization of dryer differences via operational qualification tests. AAPS PharmSciTech. 2006;7(2):E61–70. doi:10.1208/pt070239.

    Article  PubMed Central  Google Scholar 

  9. Konstantinidis AK, Kuu W, Otten L, Nail SL, Sever RR. Controlled nucleation in freeze-drying: effects on pore size in the dried product layer, mass transfer resistance, and primary drying rate. J Pharm Sci. 2011;100(8):3453–70. doi:10.1002/jps.22561.

    Article  CAS  PubMed  Google Scholar 

  10. Rasetto V, Marchisio DL, Fissore D, Barresi AA. On the use of a dual-scale model to improve understanding of a pharmaceutical freeze-drying process. J Pharm Sci. 2010;99(10):4337–50.

    Article  CAS  PubMed  Google Scholar 

  11. Ganguly A, Nail SL, Alexeenko A. Experimental determination of the key heat transfer mechanisms in pharmaceutical freeze-drying. J Pharm Sci. 2013;102(5):1610–25. doi:10.1002/jps.23514.

    Article  CAS  PubMed  Google Scholar 

  12. Patel SM, Pikal M. Process analytical technologies (PAT) in freeze-drying of parenteral products. Pharm Dev Technol. 2009;14(6):567–87. doi:10.3109/10837450903295116.

    Article  CAS  PubMed  Google Scholar 

  13. Barresi AA, Pisano R, Fissore D, Rasetto V, Velardi SA, Vallan A, et al. Monitoring of the primary drying of a lyophilization process in vials. Chem Eng Process. 2009;48(1):408–23.

    Article  CAS  Google Scholar 

  14. Fissore D, Pisano R, Barresi AA. On the methods based on the pressure rise test for monitoring a freeze-drying process. Dry Technol. 2010;29(1):73–90. doi:10.1080/07373937.2010.482715.

    Article  Google Scholar 

  15. Bosca S, Barresi AA, Fissore D. Use of a soft sensor for the fast estimation of dried cake resistance during a freeze-drying cycle. Int J Pharm. 2013;451(1–2):23–33. doi:10.1016/j.ijpharm.2013.04.046.

    Article  CAS  PubMed  Google Scholar 

  16. Bosca S, Barresi BA, Fissore D. Use of soft sensors to monitor a pharmaceuticals freeze-drying process in vials. Pharm Dev Technol. 2012;0(0):1–12. doi:10.3109/10837450.2012.757786.

    Google Scholar 

  17. Jameel F, Kessler WJ, Schneid S. Application of PAT in Real-time Monitoring and Controlling of Lyophilization Process. Quality by Design for Biopharmaceutical Drug Product Development. Springer; 2015. p. 605–47.

  18. Grant Y, Matejtschuk P, Bird C, Wadhwa M, Dalby PA. Freeze drying formulation using microscale and design of experiment approaches: a case study using granulocyte colony-stimulating factor. Biotechnol Lett. 2012;34(4):641–8. doi:10.1007/s10529-011-0822-2.

    Article  CAS  PubMed  Google Scholar 

  19. Kauppinen A, Toiviainen M, Korhonen O, Aaltonen J, Jarvinen K, Paaso J, et al. In-line multipoint near-infrared spectroscopy for moisture content quantification during freeze-drying. Anal Chem. 2013;85(4):2377–84. doi:10.1021/ac303403p.

    Article  CAS  PubMed  Google Scholar 

  20. Capelle MAH, Gurny R, Arvinte T. High throughput screening of protein formulation stability: practical considerations. Eur J Pharm Biopharm. 2007;65(2):131–48. doi:10.1016/j.ejpb.2006.09.009.

    Article  CAS  PubMed  Google Scholar 

  21. Kauppinen A, Toiviainen M, Aaltonen J, Korhonen O, Järvinen K, Juuti M, et al. Microscale freeze-drying with Raman spectroscopy as a tool for process development. Anal Chem. 2013;85(4):2109–16. doi:10.1021/ac3027349.

    Article  CAS  PubMed  Google Scholar 

  22. Capelle MAH, Arvinte T. High-throughput formulation screening of therapeutic proteins. Drug Discov Today Technol. 2008;5(2–3):e71–e9. doi:10.1016/j.ddtec.2009.03.003.

    Article  PubMed  Google Scholar 

  23. PSI. Lyoflux: Tunable Diode Laser Absorption Spectroscopy. Physical Sciences Inc., USA. 2016. http://www.psicorp.com/case-studies/lyoflux%E2%84%A2-tunable-diode-laser-absorption-spectroscopy. Accessed 20/06/2016 2016.

  24. Meister E, Gieseler H. Freeze-dry microscopy of protein/sugar mixtures: drying behavior, interpretation of collapse temperatures and a comparison to corresponding glass transition data. J Pharm Sci. 2009;98(9):3072–87. doi:10.1002/jps.21586.

    Article  CAS  PubMed  Google Scholar 

  25. Mujat M, Greco K, Galbally-Kinney KL, Hammer DX, Ferguson RD, Iftimia N, et al. Optical coherence tomography-based freeze-drying microscopy. Biomed Opt Express. 2012;3(1):55–63.

    Article  PubMed  Google Scholar 

  26. De Beer T, Burggraeve A, Fonteyne M, Saerens L, Remon JP, Vervaet C. Near infrared and Raman spectroscopy for the in-process monitoring of pharmaceutical production processes. Int J Pharm. 2010;In Press, Corrected Proof.

  27. De Beer TRM, Vercruysse P, Burggraeve A, Quinten T, Ouyang J, Zhang X, 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. J Pharm Sci. 2009;98(9):3430–46. doi:10.1002/jps.21633.

    Article  CAS  PubMed  Google Scholar 

  28. Pikal MJ, Shah S, Roy ML, Putman R. The secondary drying stage of freeze drying: drying kinetics as a function of temperature and chamber pressure. Int J Pharm. 1990;60(3):203–7.

    Article  CAS  Google Scholar 

  29. Hsu CL, Heldman DR, Taylor TA, Kramer HL. Influence of cooling rate on glass transition temperature of sucrose solutions and rice starch gel. J Food Sci. 2003;68(6):1970–5. doi:10.1111/j.1365-2621.2003.tb07003.x.

    Article  CAS  Google Scholar 

  30. Pomerantsev AL, Rodionova OY. Process analytical technology: a critical view of the chemometricians. J Chemom. 2012;26(6):299–310. doi:10.1002/cem.2445.

    Article  CAS  Google Scholar 

  31. Tang X, Nail S, Pikal M. Evaluation of manometric temperature measurement (MTM), a process analytical technology tool in freeze drying, part III: heat and mass transfer measurement. AAPS PharmSciTech. 2006;7(4):E105–E11. doi:10.1208/pt070497.

    Article  PubMed Central  Google Scholar 

  32. Gieseler H, Kramer T, Pikal M. Use of manometric temperature measurement (MTM) and SMART™ freeze dryer Technology for Development of an optimized freeze-drying cycle. J Pharm Sci. 2007;96(12):3402–18.

    Article  CAS  PubMed  Google Scholar 

  33. Tang X, Nail S, Pikal M. Evaluation of manometric temperature measurement, a process analytical technology tool for freeze-drying: part II measurement of dry-layer resistance. AAPS PharmSciTech. 2006;7(4):E77–84. doi:10.1208/pt070493.

    Article  PubMed Central  Google Scholar 

  34. Johnson RE, Oldroyd ME, Ahmed SS, Gieseler H, Lewis LM. Use of manometric temperature measurements (MTM) to characterize the freeze-drying behavior of amorphous protein formulations. J Pharm Sci. 2009;99(6):2863–73. doi:10.1002/jps.22031.

    Article  Google Scholar 

  35. Gieseler H, Kessler WJ, Finson M, Davis SJ, Mulhall PA, Bons V, et al. Evaluation of tunable diode laser absorption spectroscopy for in-process water vapor mass flux measurements during freeze drying. J Pharm Sci. 2007;96(7):1776–93. doi:10.1002/jps.20827.

    Article  CAS  PubMed  Google Scholar 

  36. Kuu WY, Nail SL, Sacha G. Rapid determination of vial heat transfer parameters using tunable diode laser absorption spectroscopy (TDLAS) in response to step-changes in pressure set-point during freeze-drying. J Pharm Sci. 2009;98(3):1136–54.

    Article  CAS  PubMed  Google Scholar 

  37. Tang X, Nail SL, Pikal MJ. Freeze-drying process design by manometric temperature measurement: Design of a smart freeze-dryer. Pharm Res. 2005;22(4):685–700. doi:10.1007/s11095-005-2501-2.

    Article  CAS  PubMed  Google Scholar 

  38. Schneid S, Gieseler H. Evaluation of a new wireless temperature remote interrogation system (TEMPRIS) to measure product temperature during freeze drying. AAPS PharmSciTech. 2008;9(3):729–39. doi:10.1208/s12249-008-9099-8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Christ M. Lyocontrol-sensor for process monitoring and for the determination of the freezing point. In: Process control and optimization. Martin Christ, Germany. 2013. Accessed October 29 2013.

  40. Rey L, May JC. Freeze-drying/lyophilization of pharmaceutical and biological products. Drugs and pharamcaceutical sciences, vol 96. New York: Marcel Dekker; 1999.

    Google Scholar 

  41. Ward KR, Matejtschuk P. The use of microscopy, thermal analysis, and impedance measurements to establish critical formulation parameters for freeze-drying cycle development. In: Rey L, May JC, editors. Freeze drying/lyophilization of pharmaceutical and biological products. New York: Marcel Dekker; 2010. p. 112–35.

    Google Scholar 

  42. Smith G, Polygalov E, Arshad MS, Page T, Taylor J, Ermolina I. An impedance-based process analytical technology for monitoring the lyophilisation process. Int J Pharm. 2013;449(1–2):72–83. doi:10.1016/j.ijpharm.2013.03.060.

    Article  CAS  PubMed  Google Scholar 

  43. Smith G, Polygalov E, Page T, inventors; GEA Pharma Systems Limited, assignee. Electrical monitoring of a lyophilization process Great Britain patent GB2480299. 2011 16/11/2011.

  44. Smith G, Arshad MS, Polygalov E, Ermolina I, Nazari K, Taylor J, et al. Through-vial impedance spectroscopy: a new in-line process analytical technology for freeze-drying. PharmTechnol. 2014;38(4):38–46.

    CAS  Google Scholar 

  45. Smith G, Arshad M, Polygalov E, Ermolina I. 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. AAPS PharmSciTech. 2014;15(2):261–9. doi:10.1208/s12249-013-0054-y.

    Article  CAS  PubMed  Google Scholar 

  46. Pikal MJ, Roy ML, Shah S. Mass and heat transfer in vial freeze-drying of pharmaceuticals: role of the vial. J Pharm Sci. 1984;73(9):1224–37. doi:10.1002/jps.2600730910.

    Article  CAS  PubMed  Google Scholar 

  47. Arshad MS, Smith G, Polygalov E, Ermolina I. Through-vial impedance spectroscopy of critical events during the freezing stage of the lyophilization cycle: the example of the impact of sucrose on the crystallization of mannitol. Eur J Pharm Biopharm. 2014;87(3):598–05. doi:10.1016/j.ejpb.2014.05.005.

    Article  CAS  PubMed  Google Scholar 

  48. Sun WQ. Temperature and viscosity for structural collapse and crystallization of amorphous carbohydrate solutions. Cryo Letters. 1997;18:99–106.

    CAS  Google Scholar 

  49. Greco K, Mujat M, Galbally-kinney KL, Hammer DX, Ferguson RD, Iftimia N, et al. Accurate prediction of collapse temperature using optical coherence tomography-based freeze-drying microscopy. J Pharm Sci. 2013;102(6):1773–85. doi:10.1002/jps.23516.

    Article  CAS  PubMed  Google Scholar 

  50. Smith G, Arshad MS, Polygalov E, Ermolina I. An application for impedance spectroscopy in the characterisation of the glass transition during the lyophilization cycle: the example of a 10% w/v maltodextrin solution. Eur J Pharm Biopharm. 2013;85(3 Pt B):1130–40. doi:10.1016/j.ejpb.2013.08.004.

    Article  CAS  PubMed  Google Scholar 

  51. James A, Searles JFC, Theodore W. Randolph. Annealing to optimize the primary drying rate, reduce freezing-induced drying rate heterogeneity, and determine Tg in pharmaceutical lyophilization. J Pharm Sci. 2000;90(7):872–87.

    Google Scholar 

  52. Smith G, Arshad MS, Polygalov E, Ermolina I. Through-vial impedance spectroscopy of the mechanisms of annealing in the freeze-drying of maltodextrin: the impact of annealing hold time and temperature on the primary drying rate. J Pharm Sci. 2014;103(6):1799–810. doi:10.1002/jps.23982.

    Article  CAS  PubMed  Google Scholar 

  53. Wei W. Lyophilization and development of solid protein pharmaceuticals. Int J Pharm. 2000;203(1–2):1–60. doi:10.1016/s0378-5173(00)00423-3.

    Google Scholar 

  54. Izutsu K-i, Aoyagi N, Kojima S. Effect of polymer size and cosolutes on phase separation of poly(vinylpyrrolidone) (PVP) and dextran in frozen solutions. J Pharm Sci. 2005;94(4):709–17. doi:10.1002/jps.20292.

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Pharmaceutical Technologies Group, Leicester School of Pharmacy, De Montfort University, Leicester, LE1 9BH, UK

    Geoff Smith, Muhammad Sohail Arshad, Eugene Polygalov & Irina Ermolina

  2. Department of Pharmacy, Bahauddin Zakariya University, Multan, Pakistan

    Muhammad Sohail Arshad

  3. Genzyme (a Sanofi Company), IDA Business Park, Old Kilmeaden Road, Waterford, Ireland

    Timothy R McCoy

  4. National Institute for Biological Standards and Control (NIBSC), South Mimms, Potters Bar, Herts, EN6 3QG, UK

    Paul Matejtschuk

Authors
  1. Geoff Smith
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Muhammad Sohail Arshad
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Eugene Polygalov
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Irina Ermolina
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Timothy R McCoy
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Paul Matejtschuk
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Geoff Smith.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Smith, G., Arshad, M.S., Polygalov, E. et al. Process Understanding in Freeze-Drying Cycle Development: Applications for Through-Vial Impedance Spectroscopy (TVIS) in Mini-pilot Studies. J Pharm Innov 12, 26–40 (2017). https://doi.org/10.1007/s12247-016-9266-5

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12247-016-9266-5

Keywords

Search

Navigation