Skip to main content
SpringerLink
Log in

Process Analytical Technology (PAT) for Lyophilization Process Monitoring and End Point Detection

  • Chapter
  • First Online:
Principles and Practices of Lyophilization in Product Development and Manufacturing

Part of the book series: AAPS Advances in the Pharmaceutical Sciences Series ((AAPS,volume 59))

  • 1078 Accesses

Abstract

Process analytical technology (PAT) is critical during freeze drying at extreme conditions (low temperature and low pressure), and latest PAT tools are reviewed in this chapter. These PAT tools are first discussed for the potential measurement of temperature, pressure, and/or mass/heat transfer, and their potential application for the endpoint detection during lyophilization is further examined. Finally, the PATs are summarized in terms of their application in both lab and large-scale lyophilizers.

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

Access this chapter

Log in via an institution

Subscribe and save

Springer+ Basic
$34.99 /Month
  • Get 10 units per month
  • Download Article/Chapter or eBook
  • 1 Unit = 1 Article or 1 Chapter
  • Cancel anytime
Subscribe now

Buy Now

Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 139.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 179.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 179.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

Similar content being viewed by others

Bibliography

  1. Rathore AS, Winkle H. Quality by design for biopharmaceuticals. Nat Biotechnol. 2009;27(1):26–34. Accessed 24 Mar 2021. https://nature.com/articles/nbt0109-26.

    Article  CAS  PubMed  Google Scholar 

  2. Patel SM, Pikal MJ. Process Analytical Technologies (PAT) in freeze-drying of parenteral products. Pharm Dev Technol. 2009;14(6):567–87. Accessed 24 Mar 2021. https://tandfonline.com/doi/full/10.3109/10837450903295116.

    Article  CAS  PubMed  Google Scholar 

  3. Beer T, De P, Vercruysse A, Burggraeve TQ, Jin Ouyang X, Zhang CV, Remon JP, Baeyens W. 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. Accessed 29 Mar 2021. https://ncbi.nlm.nih.gov/pubmed/19130604.

    Article  PubMed  Google Scholar 

  4. Wang B(S), McCoy TR. Advances in process analytical technology in freeze-drying. In: Varshney D, Singh M, editors. Lyophilized biologics and vaccines. New York: Springer; 2015. Accessed 29 Mar 2021. https://link.springer.com/chapter/10.1007/978-1-4939-2383-0_8.

    Google Scholar 

  5. Pikal MJ. Freeze-drying of proteins. Process, formulation, and stability. ChemInform. 1995;26(4). Accessed 24 Mar 2021. http://onlinelibrary.wiley.com/doi/10.1002/chin.199504315/abstract.

  6. 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. Accessed 24 Mar 2021. https://ncbi.nlm.nih.gov/pubmed/6491939.

    Article  CAS  PubMed  Google Scholar 

  7. Nail SL, Jiang S, Chongprasert S, Knopp SA. Fundamentals of freeze-drying. Pharm Biotechnol. 2002;14:281–360. Accessed 24 Mar 2021. https://ncbi.nlm.nih.gov/pubmed/12189727.

    Article  CAS  PubMed  Google Scholar 

  8. Patel SM, Doen T, Pikal MJ. Determination of end point of primary drying in freeze-drying process control. AAPS PharmSciTech. 2010;11(1):73–84. Accessed 24 Mar 2021. https://ncbi.nlm.nih.gov/pmc/articles/pmc2850457.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Schneid SC, Gieseler H, Kessler WJ, Luthra S, Luthra S, Pikal MJ. Optimization of the secondary drying step in freeze drying using TDLAS technology. AAPS PharmSciTech. 2011;12(1):379–87. Accessed 24 Mar 2021. https://ncbi.nlm.nih.gov/pmc/articles/pmc3066362.

    Article  PubMed  PubMed Central  Google Scholar 

  10. Tang X(C), Pikal MJ. Design of freeze-drying processes for pharmaceuticals: practical advice. Pharm Res. 2004;21(2):191–200. Accessed 24 Mar 2021. https://link.springer.com/article/10.1023/b:pham.0000016234.73023.75.

    Article  CAS  PubMed  Google Scholar 

  11. Konstantinidis AK, Kuu WY, 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. Accessed 24 Mar 2021. https://ncbi.nlm.nih.gov/pubmed/21465488.

    Article  CAS  PubMed  Google Scholar 

  12. Schneid SC, 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. Accessed 24 Mar 2021. https://ncbi.nlm.nih.gov/pmc/articles/pmc2977010.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Milton N, Pikal MJ, Roy ML, Nail SL. Evaluation of manometric temperature measurement as a method of monitoring product temperature during lyophilization. PDA J Pharm Sci Technol. 1997;51(1):7–16. Accessed 24 Mar 2021. https://journal.pda.org/content/51/1/7.

    CAS  PubMed  Google Scholar 

  14. Pikal MJ, Tang X(C), Nail SL. Automated process control using manometric temperature measurement. Access. 2003;3(24):2021. http://freepatentsonline.com/6971187.html.

    Google Scholar 

  15. Tang X(C), Nail SL, Nail SL, Pikal MJ. Evaluation of manometric temperature measurement, a process analytical technology tool for freeze-drying: Part I, product temperature measurement. AAPS Pharmscitech. 2006b;7(1):E95–E103. Accessed 24 Mar 2021. https://link.springer.com/article/10.1208/pt070114.

    Article  PubMed  PubMed Central  Google Scholar 

  16. Tang X(C), 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. Accessed 24 Mar 2021. https://link.springer.com/article/10.1007/s11095-005-2501-2.

    Article  CAS  PubMed  Google Scholar 

  17. Nail SL, Johnson W. Methodology for in-process determination of residual water in freeze-dried products. Dev Biol Stand. 1992;74:137–51.

    CAS  PubMed  Google Scholar 

  18. 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. Accessed 24 Mar 2021. https://sciencedirect.com/science/article/pii/037851739090074e.

    Article  CAS  Google Scholar 

  19. Rambhatla S, Ramot R, Bhugra C, Pikal MJ. Heat and mass transfer scale-up issues during freeze drying: II. Control and characterization of the degree of supercooling. AAPS PharmSciTech. 2004;5(4):54–62. Accessed 24 Mar 2021. https://link.springer.com/article/10.1208/pt050458.

    Article  PubMed Central  Google Scholar 

  20. Tang X(C), Nail SL, Pikal MJ. Evaluation of manometric temperature measurement, a process analytical technology tool for freeze-drying: Part II measurement of dry-layer resistance. AAPS PharmSciTech. 2006a;7(4):93. Accessed 24 Mar 2021. https://link.springer.com/article/10.1208/pt070493.

    PubMed  Google Scholar 

  21. Pikal MJ. Use of laboratory data in freeze drying process design: heat and mass transfer coefficients and the computer simulation of freeze drying. PDA J Pharm Sci Technol. 1985;39(3):115–39. Accessed 29 Mar 2021. https://journal.pda.org/content/39/3/115.

    CAS  Google Scholar 

  22. Mockus L, Paul TW, Pease NA, Harper NJ, Basu PK, Oslos EA, Sacha GA, et al. Quality by design in formulation and process development for a freeze-dried, small molecule parenteral product: a case study. Pharm Dev Technol. 2011;16(6):549–76. Accessed 24 Mar 2021. https://ncbi.nlm.nih.gov/pubmed/21932931.

    Article  CAS  PubMed  Google Scholar 

  23. Patel SM, Pikal MJ. Lyophilization process design space. J Pharm Sci. 2013;102(11):3883–7. Accessed 29 Mar 2021. https://sciencedirect.com/science/article/pii/s0022354915308522.

    Article  CAS  PubMed  Google Scholar 

  24. Tang XC, Nail SL, Pikal MJ. Evaluation of manometric temperature measurement (MTM), a process analytical technology tool in freeze drying, part III: heat and mass transfer measurement. AAPS PharmSciTech. 2006c;7(4):97. Accessed 24 Mar 2021. https://ncbi.nlm.nih.gov/pmc/articles/pmc2750334.

    PubMed  Google Scholar 

  25. Gieseler H, Kessler WJ, Finson ML, Davis SJ, Mulhall PA, Bons V, Debo DJ, Pikal MJ. 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. Accessed 29 Mar 2021. https://ncbi.nlm.nih.gov/pubmed/17221854.

    Article  CAS  PubMed  Google Scholar 

  26. Schneid SC, Gieseler H, Kessler WJ, Pikal MJ. Non-invasive product temperature determination during primary drying using tunable diode laser absorption spectroscopy. J Pharm Sci. 2009;98(9):3406–18. Accessed 29 Mar 2021. https://ncbi.nlm.nih.gov/pubmed/18781643.

    Article  CAS  PubMed  Google Scholar 

  27. Sharma P, Kessler WJ, Bogner RH, Thakur MS, Pikal MJ. Applications of the tunable diode laser absorption spectroscopy: in-process estimation of primary drying heterogeneity and product temperature during lyophilization. J Pharm Sci. 2019;108(1):416–30. Accessed 29 Mar 2021. https://sciencedirect.com/science/article/pii/s0022354918305008.

    Article  CAS  PubMed  Google Scholar 

  28. Kuu WY, Nail SL. Rapid freeze-drying cycle optimization using computer programs developed based on heat and mass transfer models and facilitated by tunable diode laser absorption spectroscopy (TDLAS). J Pharm Sci. 2009;98(9):3469–82. Accessed 29 Mar 2021. https://sciencedirect.com/science/article/abs/pii/s0022354916330532.

    Article  CAS  PubMed  Google Scholar 

  29. Kuu WY, Nail SL, Sacha GA. 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. Accessed 29 Mar 2021. https://sciencedirect.com/science/article/abs/pii/s0022354916329148.

    Article  CAS  PubMed  Google Scholar 

  30. Roy ML, Pikal MJ. Process control in freeze drying: determination of the end point of sublimation drying by an electronic moisture sensor. PDA J Pharm Sci Technol. 1989;43(2):60–6. Accessed 29 Mar 2021. https://journal.pda.org/content/43/2/60.

    CAS  Google Scholar 

  31. Connelly JP, Welch JV. Monitor lyophilization with mass spectrometer gas analysis. PDA J Pharm Sci Technol. 1993;47(2):70–5. Accessed 29 Mar 2021. https://ncbi.nlm.nih.gov/pubmed/8515347.

    CAS  Google Scholar 

  32. Ganguly A, Stewart J, Rhoden A, Volny M, Saad N. Mass spectrometry in freeze-drying: motivations for using a bespoke PAT for laboratory and production environment. Eur J Pharm Biopharm. 2018;127:298–308. Accessed 29 Mar 2021. https://sciencedirect.com/science/article/pii/s0939641117314303.

    Article  CAS  PubMed  Google Scholar 

  33. Weiland A, Mangold A. Lyocylce optimization- “Hot” and “Cold” spot determination (HTC) using TEMPRIS for wireless real-time temperature measurement as process analytical technology (PAT) tool - presenting a production scale performance qualification case study. CPPR freeze drying of pharmaceuticals and biologicals. Garmisch-Partenkirchen (Germany). 2014.

    Google Scholar 

Download references

Author information

Authors and Affiliations

  1. CMC Management, WuXi Biologics, Greater Boston Area, MA, USA

    Bingquan (Stuart) Wang

  2. Formulation Development, Regeneron Pharmaceuticals Inc., Tarrytown, NY, USA

    Xiaolin (Charlie) Tang

Authors
  1. Bingquan (Stuart) Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Xiaolin (Charlie) Tang
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Bingquan (Stuart) Wang .

Editor information

Editors and Affiliations

  1. Nimble BioSolutions, Gurnee, IL, USA

    Feroz Jameel

Rights and permissions

Reprints and permissions

Copyright information

© 2023 America Association of Pharmaceutical Scientists

About this chapter

Check for updates. Verify currency and authenticity via CrossMark

Cite this chapter

Wang, B.(., Tang, X.(. (2023). Process Analytical Technology (PAT) for Lyophilization Process Monitoring and End Point Detection. In: Jameel, F. (eds) Principles and Practices of Lyophilization in Product Development and Manufacturing . AAPS Advances in the Pharmaceutical Sciences Series, vol 59. Springer, Cham. https://doi.org/10.1007/978-3-031-12634-5_20

Download citation

Publish with us

Policies and ethics

Search

Navigation