Skip to main content
SpringerLink
Log in

Multivariate Analysis for Process Understanding, Monitoring, Control, and Optimization of Lyophilization Processes

  • Chapter
  • First Online:
Quality by Design for Biopharmaceutical Drug Product Development

Part of the book series: AAPS Advances in the Pharmaceutical Sciences Series ((AAPS,volume 18))

Abstract

The biopharmaceutical industry has entered a new era. Attention is now being paid to real-time process monitoring, real-time process control, continuous improvement of processes, and quick product technology transfer. Terms like Quality by Design (QbD), design space, control strategy, process analytical technology, process signature are now used to reflect the current state. Multivariate statistical analysis has played an integral part in several industries, enabling process understanding, utilization of real-time analyzers, and real-time product release. It is therefore appropriate to see it as an integral part of the biopharmaceutical industry effort to address issues like design space, control strategy, real-time process signature monitoring, process understanding, and correct technology transfer. This chapter discusses the fundamentals behind multivariate methods for such purposes.

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

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 189.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 249.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 249.99
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

References

  • Albert S, Kinley RD (2001) Multivariate statistical monitoring of batch processes: an industrial case study of fermentation supervision. Trends Biotechnol 19:53–62

    Article  CAS  PubMed  Google Scholar 

  • Bai S, Nayar R, Carpenter JF, Manning MC (2005) Non-invasive determination of protein conformation in the solid state using near infrared (NIR) spectroscopy. J Pharm Sci 94(9):2030–2038

    Google Scholar 

  • Barresi AA, Velardi SA, Pisano R, Rasetto V, Vallan A, Galan M (2009) In-line control of the lyophilization process. A gentle PAT approach using software sensors. Int J Refrig 32:1003–1014

    Article  CAS  Google Scholar 

  • Bosca S, Fissore D (2014) Monitoring of a pharmaceuticals freeze-drying process by model-based process analytical technology tools. Chem Eng Technol 37(2):240–248

    Article  CAS  Google Scholar 

  • Brülls M, Folestad S, Sparén A, Rasmuson A (2003) In-situ near-infrared spectroscopy monitoring of the lyophilization process. Pharm Res 20(3):494–499

    Google Scholar 

  • Burnham AJ, Viveros R, MacGregor JF (1996) Frameworks for latent variable multivariate regression. J Chemom 10:31–45

    Article  CAS  Google Scholar 

  • De Beer TR, Allesø M, Goethals F, Coppens A, Heyden YV, De Diego HL, Rantanen J, Verpoort F, Vervaet C, Remon JP, Baeyens WR (2007) Implementation of a process analytical technology system in a freeze-drying process using Raman spectroscopy for in-line process monitoring. Anal Chem 79(21):7992–8003

    Article  CAS  PubMed  Google Scholar 

  • De Beer TRM, Vercruysse P, Burggraeve A, Quinten T, Ouyang J, x Zhang X, Vervaet C, Remon JP, Baeyens WRG (2009) 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 98(9):3430–3446

    Google Scholar 

  • Duchesne C, MacGregor JF (2000) Multivariate analysis and optimization of process variable trajectories for batch processes. Chemom Intell Lab Syst 51:125–137

    Google Scholar 

  • Duchesne C, MacGregor JF (2004) Establishing multivariate specification regions for incoming materials. J Qual Technol 36:78–94

    Google Scholar 

  • Fissore D, Velardi S, Barresi A (2008) In-line control of a freeze-drying process in vials. Dry Technol 26(6):685–694 (10)

    Google Scholar 

  • Fissore D, Pisano R, Barresi AA (2011) Advanced approach to build the design space for the primary drying of a pharmaceutical freeze-drying process. J Pharm Sci, Wiley on-line, doi:10.1002/jps.22668

    Google Scholar 

  • Flores-Cerrillo J, MacGregor JF (2004) Control of batch product quality by trajectory manipulation using latent variable models. J Proc Control 14:539–553

    Article  CAS  Google Scholar 

  • García-Muñoz S, Kourti T, MacGregor JF, Mateos AG, Murphy G (2003) Troubleshooting of an industrial batch process using multivariate methods. Ind Eng Chem Res 42:3592–3601

    Article  Google Scholar 

  • García-Muñoz S, MacGregor JF, Kourti T (2004) Model predictive monitoring for batch processes with multivariate methods. Ind Eng Chem Res 43:5929–5941

    Article  Google Scholar 

  • García-Muñoz S, MacGregor JF, Kourti T (2005) Product transfer between sites using joint Y_PLS. Chemom Intell Lab Syst 79:101–114

    Google Scholar 

  • García-Muñoz S, Kourti T, MacGregor JF, Apruzzece F, Champagne M (2006) Optimization of batch operating policies, Part I—handling multiple solutions. Ind Eng Chem Res 45:7856–7866

    Article  Google Scholar 

  • García–Muñoz S, MacGregor JF, Neogi D, Latshaw BE, Mehta S (2008) Optimization of batch operating policies. Part II. Incorporating process constraints and industrial applications. Ind Eng Chem Res 47:4202–4208

    Article  Google Scholar 

  • González-Martínez JM, Ferrer A, Westerhuis JA (2011) Real-time synchronization of batch trajectories for on-line multivariate statistical process control using dynamic time warping. Chemom Intell Lab Syst 105:195–206

    Article  Google Scholar 

  • Grohganz H, Fonteyne M, Skibsted E, Falck T, Palmqvist B, Rantanen J (2010) Classification of lyophilised mixtures using multivariate analysis of NIR spectra. Eur J Pharm Biopharm 74:406–412

    Article  CAS  PubMed  Google Scholar 

  • ICH (2011) Quality implementation working group points to consider (R2), December 2011. http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Quality/Q8_9_10_QAs/PtC/Quality_IWG_PtCR2_6dec2011.pdf

  • Jackson JE (1991) A user’s guide to principal components. Wiley, New York

    Book  Google Scholar 

  • Jameel F, Kessler WJ (2011) Real-time monitoring and controlling of lyophilization process parameters through process analytical technology tools. In PAT applied in biopharmaceutical process development and manufacturing: an enabling tool for quality-by-design. In Undey C, Low D, Menezes JC, Koch M (eds) Biotechnology and bioprocessing series, T & F CRC Press, New York, ISBN: 9781439829455

    Google Scholar 

  • Jorgensen JP, Pedersen JG, Jensen EP, Esbensen K (2004) On-line batch fermentation process monitoring—introducing biological process time. J Chemom 18:1–11

    Article  Google Scholar 

  • Kassidas A, MacGregor JF, Taylor PA (1998) Synchronization of batch trajectories using dynamic time warping. AIChE J 44:864–875

    Article  CAS  Google Scholar 

  • Katayama DS, Kirchhoff CF, Elliott CM, Johnson RE, Borgmeyer J, Thiele BR, Zeng DL, Hong Qi, Ludwig JD, Manning MC (2004) Retrospective statistical analysis of lyophilized protein formulations of progenipoietin using PLS: determination of the critical parameters for long-term storage stability. J Pharm Sci 93(10):2609–2623

    Article  CAS  PubMed  Google Scholar 

  • Koganti VR, Shalaev EY, Berry MR, Osterberg T, Youssef M, Hiebert DN, Kanka FA, Nolan M, Barrett R, Scalzo G, Fitzpatrick G, Fitzgibbon N, Luthra S, Zhang L (2011) Investigation of design space for freeze-drying: use of modeling for primary drying segment of a freeze-drying cycle. AAPS Pharm Sci Tech 12(3):854–861

    Google Scholar 

  • Kourti T (2003a) Multivariate dynamic data modeling for analysis and statistical process control of batch processes, start-ups and grade transitions. J Chemom 17:93–109

    Article  CAS  Google Scholar 

  • Kourti T (2003b) Abnormal situation detection, three way data and projection methods—robust data archiving and modeling for industrial applications. Ann Rev Control 27(2):131–138

    Google Scholar 

  • Kourti T (2005a) Application of latent variable methods to process control and multivariate statistical process control in industry. Int J Adapt Control Signal Proc 19:213–246

    Article  Google Scholar 

  • Kourti T (2009) Multivariate statistical process control and process control, using latent variables. In: Brown S, Tauler R, Walczak R (eds) Comprehensive chemometrics, vol 4. Elsevier, Oxford, pp 21–54

    Chapter  Google Scholar 

  • Kourti T (2010) Pharmaceutical manufacturing: the role of multivariate analysis in design space. Control strategy, process understanding, troubleshooting, optimization. In David J et al (ed) Chemical engineering in the pharmaceutical industry: R & D to manufacturing. Wiley, pp 853–878

    Google Scholar 

  • Kourti T, MacGregor JF (1995) Process analysis, monitoring and diagnosis using multivariate projection methods—a tutorial. Chemom Intell Lab Syst 28:3–21

    Google Scholar 

  • Kourti T, Nomikos P, MacGregor JF (1995) Analysis, monitoring and fault diagnosis of batch processes using multiblock and multiway PLS. J Process Control 5(4):277–284

    Article  CAS  Google Scholar 

  • Kourti T, Lee J, MacGregor JF (1996) Experiences with industrial applications of projection methods for multivariate statistical process control. Comput Chem Eng 20(Suppl):S745–S750

    Google Scholar 

  • Kundu S, Bhatnagar V, Pathak N, Undey C (2010) Chemical engineering principles in biologics: unique challenges and applications. In: David J et al (eds) Chemical engineering in the pharmaceutical industry: R & D to manufacturing. Wiley, pp 29–55

    Google Scholar 

  • MacGregor JF, Kourti T, Kresta JV (1991) Multivariate identification: a study of several methods. In Najim K, Babary JP (eds) International symposium on advanced control of chemical processes ADCHEM ’91 (an IFAC Symposium). Toulouse, France, October 14–16, pp 369–375

    Google Scholar 

  • Maltesen MJ, Bjerregaard S, Hovgaard L, Havelund S, van de Weert M, Grohganz H (2011) Multivariate analysis of phenol in freeze-dried and spray-dried insulin formulations by NIR and FTIR. AAPS Pharm Sci Tech 12(2):627–635

    Google Scholar 

  • Marjanovic O, Lennox B, Sandoz D, Smith K, Crofts M (2006) Real-time monitoring of an industrial batch process, presented at CPC7: chemical process control. Lake Louise Alberta, Canada

    Google Scholar 

  • Menezes JC, Ferreira AP, Rodrigues LO, Brás LP, Alves TP (2009) Chemometrics role within the PAT context: examples from primary pharmaceutical manufacturing. In: Brown S, Tauler R, Walczak R (eds) Comprehensive chemometrics, vol 4. Elsevier, Oxford, pp 313–355

    Google Scholar 

  • Mockus L, LeBlond D, Basu PK, Shah RB, Khan MA (2011) A QbD case study: Bayesian prediction of lyophilization cycle parameters. AAPS Pharm Sci Tech 12(1):442–448

    Google Scholar 

  • Muzzio CR, Nicolás Dini G, Simionato LD (2011) Determination of moisture content in lyophilized mannitol through intact glass vials using NIR micro-spectrometers. Braz J Pharm Sci 47(2):289–297

    Google Scholar 

  • Neogi D, Schlags CE (1998) Multivariate statistical analysis of an emulsion batch process. Ind Eng Chem Res 37:3971–3979

    Article  CAS  Google Scholar 

  • Nomikos P (1995) Statistical process control of batch processes. Ph.D. thesis, McMaster University, Hamilton, Canada

    Google Scholar 

  • Nomikos P, MacGregor JF (1994) Monitoring of batch processes using multi-way principal component analysis. AlChE J 40(8):1361–1375

    Article  CAS  Google Scholar 

  • Nomikos P, MacGregor JF (1995a) Multivariate SPC charts for monitoring batch processes. Technometrics 37(1):41–59

    Article  Google Scholar 

  • Nomikos P, MacGregor JF (1995b) Multiway partial least squares in monitoring batch processes. Chemom Intell Lab Syst 30:97–108

    Google Scholar 

  • Patel SM, Doen T, Pikal MJ (2010) Determination of end point of primary drying in freeze-drying process control. AAPS Pharm Sci Tech 11(1):73–84

    Google Scholar 

  • Rambhatla S, Tchessalov S, Pikal MJ (2006) Heat and mass transfer scale-up issues during freeze-drying, III: control and characterization of dryer differences via operational qualification tests. AAPS Pharm Sci Tech 7(2):Article 39

    Google Scholar 

  • Taylor PA (1998) Computing and software dept., McMaster University, Hamilton, Ontario, Canada (May 1998), personal communication

    Google Scholar 

  • Ãœndey C, Ertunç S, Çınar A (2003) Online batch/fed-batch process performance monitoring, quality prediction, and variable-contribution analysis for diagnosis. Ind Eng Chem Res 42(20):4645–4658

    Article  Google Scholar 

  • Westerhuis JA, Kourti T, MacGregor JF (1998) Analysis of multiblock and hierarchical PCA and PLS models. J Chemom 12:301–321

    Article  CAS  Google Scholar 

  • Westerhuis JA, Kourti T, MacGregor JF (1999a) Comparing alternative approaches for multivariate statistical analysis of batch process data. J Chemom 13:397–413

    Article  CAS  Google Scholar 

  • Westerhuis JA, Kassidas A, Kourti T, Taylor PA, MacGregor JF (1999b) On-line synchronization of the trajectories of process variables for monitoring batch processes with varying duration, presented at the 6th Scandinavian Symposium on Chemometrics, Porsgrunn, Norway, Aug. 15–19

    Google Scholar 

  • Wold S (1978) Cross-validatory estimation of the number of components in factor and principal components model. Technometrics 20(4):397–405

    Article  Google Scholar 

  • Wold S, Kettaneh N, Fridén H, Holmberg A (1998) Modeling and diagnostics of batch processes and analogous kinetic experiments. Chemom Intell Lab Syst 44:331–340

    Google Scholar 

  • Yip WL, Gausemel I, Sande SA, Dyrstad K (2012) Strategies for multivariate modeling of moisture content in freeze-dried mannitol-containing products by near-infrared spectroscopy. J Pharm Biomed Anal 70:202–211

    Article  CAS  PubMed  Google Scholar 

  • Zhang H, Lennox B (2004) Integrated condition monitoring and control of fed-batch fermentation processes. J Proc Control 14:41–50

    Article  CAS  Google Scholar 

  • Zhang Y, Dudzic M, Vaculik V (2003) Integrated monitoring solution to start-up and run-time operations for continuous casting. Ann Rev Control 27:141–149

    Article  CAS  Google Scholar 

Download references

Acknowledgements

I would like to thank my colleagues in GSK; Massimo Rastelli, Yves Mayeresse, and Benoît Moreau for technical discussions regarding the lyophilization process and my line management, Gordon Muirhead and Bernadette Doyle for their continuous support.

Author information

Authors and Affiliations

  1. Global Manufacturing & Supply, GSK, Priory Street, Ware, SG12 ODJ, London, UK

    Dr. Theodora Kourti PhD

Authors
  1. Dr. Theodora Kourti PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Theodora Kourti PhD .

Editor information

Editors and Affiliations

  1. Parenteral Product and Process Development, Amgen Inc., Thousand Oaks, California, USA

    Feroz Jameel

  2. Bill and Melinda Gates Foundation, Chemistry, Manufacturing and Controls, Seattle, Washington, USA

    Susan Hershenson

  3. Division of Product Quality Research, Food and Drug Administration, Center for Drug Evaluation and Research, Office of Testing and Research and Office of Pharmaceutical Sciences, Silver Spring, Maryland, USA

    Mansoor A. Khan

  4. Enterprise Catalyst Group Inc., Palo Alto, California, USA

    Sheryl Martin-Moe

Rights and permissions

Reprints and permissions

Copyright information

© 2015 Springer Science+Business Media, LLC

About this chapter

Cite this chapter

Kourti, T. (2015). Multivariate Analysis for Process Understanding, Monitoring, Control, and Optimization of Lyophilization Processes. In: Jameel, F., Hershenson, S., Khan, M., Martin-Moe, S. (eds) Quality by Design for Biopharmaceutical Drug Product Development. AAPS Advances in the Pharmaceutical Sciences Series, vol 18. Springer, New York, NY. https://doi.org/10.1007/978-1-4939-2316-8_22

Download citation

Publish with us

Policies and ethics

Search

Navigation