Skip to main content
SpringerLink
Log in

Automation and High-Throughput Technologies in Biopharmaceutical Drug Product Development with QbD Approaches

  • 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

Quality by Design (QbD) of biopharmaceuticals assumes that desired properties of the final drug product can be predicted with the help of various analytical and characterization methods during the development process. This should be translated into a sound, scientific understanding of drug behavior to design a stability space with clearly defined parameters that produce acceptable product quality attributes. In the QbD framework, the combination and interaction of multiple input variables that have been demonstrated to provide assurance of quality is called the design space. Approaches for identifying the design space in the biopharmaceutical industry generally rely on statistical design of experiments (DOEs) which can be resource intensive (Horvath et al., Mol Biotechnol 45(3):203–206, 2010; Ng and Rajagopalan, Quality by design for biopharmaceuticals: perspectives and case studies, Wiley, Hoboken, 2009). In cases where the number of variables is large, performing a full factorial DOE may be resource intensive. The automated high-throughput methods have been found to be useful in exploration of multiple conditions, defined by so many variables. In this chapter, we describe the use of QbD for applications of automation and high-throughput technology in biopharmaceutical processes from early molecular assessment to the late stages of commercial drug development. High-throughput techniques reinforce the QbD approach not only by providing a large pool of data points using minimal resources but also by obtaining comparable and structural results, which allow thorough statistical analysis.

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

  • Ahmad SS, Dalby PA (2010) Thermodynamic parameters for salt-induced reversible protein precipitation from automated microscale experiments. Biotechnol Bioeng 108(2):322–332

    Article  Google Scholar 

  • Ahrer K, Jungbauer A (2006) Chromatographic and electrophoretic characterization of protein variants. J Chromatogr B Analyt Technol Biomed Life Sci 841:110–122

    Article  CAS  PubMed  Google Scholar 

  • Albert S, Kinley RD (2001) Multivariate statistical monitoring of batch processes: an industrial case study in fed-batch fermentation supervision. Trends Biotechnol 19(2):53–62

    Article  CAS  PubMed  Google Scholar 

  • American National Standard Institute (2004) ANSI/SBS 1-2004, 1/27/2006

    Google Scholar 

  • Ausar SF, Chan J, Hoque W et al (2011) Application of extrinsic fluorescence spectroscopy for the high throughput formulation screening of aluminum-adjuvanted vaccines. J Pharm Sci 100(2):431–440

    Article  CAS  PubMed  Google Scholar 

  • Awotwe-Otoo D, Agarabia C, Wu GK et al (2012) Quality by design: impact of formulation variables and their interactions on quality attributes of a lyophilized monoclonal antibody. Int J Pharm 438:167–175

    Article  CAS  PubMed  Google Scholar 

  • Bajaj H, Sharma VK, Kalonia DS (2007) A high-throughput method for detection of protein self-association and second virial coefficient using size-exclusion chromatography through simultaneous measurement of concentration and scattered light intensity. Pharm Res 24(11):2071–2083

    Article  CAS  PubMed  Google Scholar 

  • Banks DD, Latypov RF, Ketchem RR et al (2012) Native-state solubility and transfer free energy as predictive tools for selecting excipients to include in protein formulation development studies. J Pharm Sci 101(8):2720–2732

    Article  CAS  PubMed  Google Scholar 

  • Bhambhani A, Kissmann JM, Joshi SB et al (2012) Formulation design and high-throughput excipient selection based on structural integrity and conformational stability of dilute and highly concentrated IgG1 monoclonal antibody solutions. J Pharm Sci 101(3):1120–1135

    Article  CAS  PubMed  Google Scholar 

  • Capelle MAH, Gurny RR, Arvinte TA, Tudor A (2009) High throughput protein formulation platform: case study of salmon calcitonin. Pharm Res 26(1):118–128

    Article  CAS  PubMed  Google Scholar 

  • Castillo V, Graña-Montes R, Sabate R et al (2011) Prediction of the aggregation propensity of proteins from the primary sequence: aggregation properties of proteomes. Biotechnol J 6(6):674–685

    Article  CAS  PubMed  Google Scholar 

  • Chelius D, Jing K, Lueras A et al (2006) Formation of pyroglutamic acid from N-terminal glutamic acid in immunoglobulin gamma antibodies. Anal Chem 78:2370–2376

    Article  CAS  PubMed  Google Scholar 

  • Chelius D, Xiao G, Nichols AC et al (2008) Automated tryptic digestion procedure for HPLC/MS/MS peptide mapping of immunoglobulin gamma antibodies in pharmaceutics. J Pharm Biomed Anal 47:285–294

    Article  CAS  PubMed  Google Scholar 

  • Chollangi S, Jaffe NE, Cai H et al (2014) Accelerating purification process development of an early phase MAb with high-throughput automation. BioProcess Int 12(3):48–52

    CAS  Google Scholar 

  • Colandene J (2010) Challenges of biopharmaceutical bulk drug substance freeze-thaw, storage, and transport. 39th ACS National Meeting, San Francisco, CA, United States, March 21–25, BIOT-322

    Google Scholar 

  • del la Guntin˜as M, Wissiack R, Bordin G (2003) Determination of haemoglobin A(1c) by liquid chromatography using a new cation-exchange column. J Chromatogr B Analyt Technol Biomed Life Sci 791:73–83

    Article  Google Scholar 

  • del Val IJ et al (2010) Towards the implementation of quality by design to the production of therapeutic monoclonal antibodies with desired glycosylation patterns. Biotechnol Prog 26:1505–1527

    Article  PubMed  Google Scholar 

  • Fesinmeyer RM, Hogan S, Saluja A (2009) Effect of ions on agitation and temperature-induced aggregation reactions of antibodies. Pharm Res 26(4):903–913

    Article  CAS  PubMed  Google Scholar 

  • Gibson TJ, Mccarty K, McFadyen IJ et al (2011) Application of a high-throughput screening procedure with PEG-induced precipitation to compare relative protein solubility during formulation development with IgG1 monoclonal antibodies. J Pharm Sci 100(3):1009–1021

    Article  CAS  PubMed  Google Scholar 

  • Goldberg DS, Bishop SM, Shah AU et al (2011) Formulation development of therapeutic monoclonal antibodies using high-throughput fluorescence and static light scattering techniques: role of conformational and colloidal stability. J Phar Sci 100(4):1306–1315

    Article  CAS  Google Scholar 

  • Hamrang Z, Rattray NJW, Pluen A (2013) Proteins behaving badly: emerging technologies in profiling biopharmaceutical aggregation. Trends Biotechnol 31(8):448–458

    Article  CAS  PubMed  Google Scholar 

  • He F, Litowski J, Narhi LO et al (2010a) High-throughput dynamic light scattering method for measuring viscosity of concentrated protein solutions. Anal Biochem 399:141–143

    Article  CAS  PubMed  Google Scholar 

  • He F, Hogan S, Latypov RF, Narhi LO, Razinkov VI (2010b) High throughput thermostability screening of monoclonal antibody formulations. J Pharm Sci 99(4):1707–1720

    CAS  PubMed  Google Scholar 

  • He F, Woods CE, Trilisky E et al (2011a) Screening of monoclonal antibody formulations based on high-throughput thermostability and viscosity measurements: design of experiment and statistical analysis. J Pharm Sci 100(4):1330–1340

    Article  CAS  PubMed  Google Scholar 

  • He F, Woods CE, Becker GW et al (2011b) High-throughput assessment of thermal and colloidal stability parameters for monoclonal antibody formulations. J Pharm Sci 100:5126–5141

    Article  CAS  PubMed  Google Scholar 

  • Hiratsuka A, Yokoyama K (2009) Fully automated two-dimensional electrophoresis system for high-throughput protein analysis. Methods Mol Biol 577:155–166

    Article  CAS  PubMed  Google Scholar 

  • Horvath B, Mun M, Laird MW (2010) Characterization of a monoclonal antibody cell culture production process using a quality by design approach. Mol Biotechnol 45(3):203–206

    Article  CAS  PubMed  Google Scholar 

  • Hsu YR, Chang WC, Mendiaz EA et al (1998) Selective deamidation of recombinant human stem cell factor during in vitro aging: isolation and characterization of the aspartyl and isoaspartyl homodimers and heterodimers. Biochemistry 37:2251–2262

    Article  CAS  PubMed  Google Scholar 

  • Jezek J, Rides M, Derham B et al (2011) Viscosity of concentrated therapeutic protein compositions. Adv Drug Deliv Rev 63(13):1107–1117

    Article  CAS  PubMed  Google Scholar 

  • Johnson DH, Parupudi A, Wilson W (2009) High-throughput self-Interaction chromatography: applications in protein formulation prediction. Pharm Res 26(2):296–305

    Article  CAS  PubMed  Google Scholar 

  • Junyan AJI, Boyan Z, Wilson CY et al (2009) Tryptophan, and histidine oxidation in a model protein, PTH: mechanisms and stabilization. J Pharm Sci 98 (12):4485–4500

    Article  Google Scholar 

  • Kamath, L (2006) Practical technologies for lyophilization. Gen Eng Biotechnol News 26(20):1–4

    Google Scholar 

  • Kang SH, Gong X, Yeung ES (2000) High-throughput comprehensive peptide mapping of proteins by multiplexed capillary electrophoresis. Anal Chem 72:3014–3021

    Article  CAS  PubMed  Google Scholar 

  • Li Y, Mach H, Blue JT, (2011) High throughput formulation screening for global aggregation behaviors of three monoclonal antibodies. J Pharm Sci 100(6):2120–2135

    Article  CAS  PubMed  Google Scholar 

  • Ludwig DB et al (2011) Flow cytometry: a promising technique for the study of silicone oil-induced particulate formation in protein formulations. Anal Biochem 410:191–199

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Mach H et al (2011) The use of flow cytometry for the detection of subvisible particles in therapeutic protein formulations. J Pharm Sci 100:1671–1678

    Article  CAS  PubMed  Google Scholar 

  • MacGregor JF, Kourti T (1995) Statistical process control of multivariate processes. Control Eng Pract 3:403–414

    Article  Google Scholar 

  • Mahler H-C et al (2009) Protein aggregation: pathways, induction factors and analysis. J Pharm Sci 98:2909–2934

    Article  CAS  PubMed  Google Scholar 

  • Majors RE (2005) New developments in microplates for biological assays and automated sample preparation. LC-GC Eur 18(2):72–76

    Google Scholar 

  • Mazur MT, Seipert RS, Mahon D et al (2012) A platform for characterizing therapeutic monoclonal antibody breakdown products by 2D chromatography and top-down mass spectrometry. AAPS J 14:530–541

    Google Scholar 

  • Mungikar A, Kamat M (2010) Use of In-line Raman spectroscopy as a non-destructive and rapid analytical technique to monitor aggregation of a therapeutic protein. Am Pharm Rev 13(7):78

    Google Scholar 

  • Ng K, Rajagopalan N (2009) Application of quality by design and risk assessment principles for the development of formulation design space. In: Rathore AS, Mhatre R (eds) Quality by design for biopharmaceuticals: perspectives and case studies. Wiley, Hoboken

    Google Scholar 

  • Pantoliano MW, Petrella EC, Kwasnoski JD et al (2001) High-density miniaturized thermal shift assays as a general strategy for drug discovery. J Biomol Screen 6:429–440

    Article  CAS  PubMed  Google Scholar 

  • Rathore AS, Winkle H (2009) Quality by design for biopharmaceuticals. Nat Biotechnol 27:26–34

    Article  CAS  PubMed  Google Scholar 

  • Razinkov VI, Treuheit MJ, Becker GW (2013) Methods of high throughput biophysical characterization in biopharmaceutical development. Curr Drug Discov Technol 10(1):59–70

    CAS  PubMed  Google Scholar 

  • Roessner D, Scherrers R (2012) Formulation in high throughput. Aggregation behavior, solubility and viscosity of proteins. LaborPraxis 36(1/2):34–36

    CAS  Google Scholar 

  • Saluja A, Fesinmeyer RM, Hogan S et al (2010) Diffusion and sedimentation interaction parameters for measuring the second virial coefficient and their utility as predictors of protein aggregation. Biophys J 99:2657–2665

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Santora LC, Krull IS, Grant K (1999) Characterization of recombinant human monoclonal tissue necrosis factor-alpha antibody using cation-exchange HPLC and capillary isoelectric focusing. Anal Biochem 275:98–108

    Article  CAS  PubMed  Google Scholar 

  • Stackhouse N, Miller AK, Gadgil HS (2011) A high-throughput UPLC method for the characterization of chemical modifications in monoclonal antibody molecules. J Pharm Sci 100:5115–5125

    Article  CAS  PubMed  Google Scholar 

  • Shah RB, Tawakkul MA, Khan MA (2007) Process analytical technology: chemometric analysis of Raman and near infrared spectroscopic data for predicting physical properties of extended release matrix tablets. J Pharm Sci 96(5):1356–65

    Article  CAS  PubMed  Google Scholar 

  • Sitton G, Srienc F (2008) Mammalian cell culture scale-up and fed-batch control using automated flow cytometry. J Biotechnol 135:174–180

    Article  CAS  PubMed  Google Scholar 

  • Taylor PB, Ashman S, Baddeley SM et al (2002) A standard operating procedure for assessing liquid handler performance in high-throughput screening. J Biomol Screen 7(6):554–569

    Article  CAS  PubMed  Google Scholar 

  • Tsolis AC, Papandreou NC, Iconomidou VA et al (2013) A consensus method for the prediction of ‘aggregation-prone’ peptides in globular proteins PLoS One 8(1):e54175

    Article  PubMed Central  CAS  PubMed  Google Scholar 

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

    Article  Google Scholar 

  • Undey C, Ertunc S, Mistretta T, Looze B (2010) Applied advanced process analytics in biopharmaceutical manufacturing: challenges and prospects in real-time monitoring and control. J Process Control 20(9):1009–1018

    Article  Google Scholar 

  • Valente JJ, Payne RW, Manning MC, Wilson WW, Henry CS (2005) Colloidal behavior of proteins: effects of the second virial coefficient on solubility, crystallization and aggregation of proteins in aqueous solution. Curr Pharm Biotechnol 6(6):427–436

    Article  CAS  PubMed  Google Scholar 

  • Walsh G (2010) Biopharmaceutical benchmarks. Nat Biotechnol 28:917–924

    Article  CAS  PubMed  Google Scholar 

  • Walter TS, Ren J, Tuthill TJ et al (2012) A plate-based high-throughput assay for virus stability and vaccine formulation. J Virol Methods 185(1):166–170

    Article  PubMed Central  CAS  PubMed  Google Scholar 

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

    Article  CAS  Google Scholar 

  • Yadav S, Laue TM, Kalonia DS et al (2012) The influence of charge distribution on self-association and viscosity behavior of monoclonal antibody solutions. Mol Pharm 9(4):791–802

    Article  CAS  PubMed  Google Scholar 

  • Yamniuk AP, Ditto N, Patel M et al (2013) Application of a kosmotrope-based solubility assay to multiple protein therapeutic classes indicates broad use as a high-throughput screen for protein therapeutic aggregation propensity. J Pharm Sci 102:2424–2439

    Article  CAS  PubMed  Google Scholar 

  • Zolls S et al (2012) Particles in therapeutic protein formulations. Part 1: overview of analytical methods. J Pharm Sci 101:914–935

    Article  PubMed  Google Scholar 

Download references

Acknowledgments

Authors would like to thank Chris Garvin, William Valentine, Idalisse Gonzales, Jose Vidal, and Gloria Ruiz of Amgen related to providing data and information for real-time multivariate monitoring of fill and finish operations.

Author information

Authors and Affiliations

  1. Drug Product Development, Amgen Inc., Seattle, WA, USA

    Vladimir Razinkov & Jerry Becker

  2. Drug Product Engineering, Amgen, Inc., Thousand Oaks, CA, USA

    Cenk Undey, Erwin Freund & Feroz Jameel

Authors
  1. Vladimir Razinkov
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Jerry Becker
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Cenk Undey
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Erwin Freund
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Feroz Jameel
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Feroz Jameel .

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

Razinkov, V., Becker, J., Undey, C., Freund, E., Jameel, F. (2015). Automation and High-Throughput Technologies in Biopharmaceutical Drug Product Development with QbD Approaches. 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_20

Download citation

Publish with us

Policies and ethics

Search

Navigation