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Continuous Manufacturing of a Polymer Stabilized Emulsion Monitored with Process Analytical Technology

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Abstract

Moving from batch to continuous manufacturing (CM) requires implementation of process analytical technology (PAT), as it is crucial to monitor and control these processes. CM of semi-solids has been demonstrated but implementation of a broader range of PAT tools with in- or on-line process interfacing at the end of the CM line has not been demonstrated. The goal of this work was to continuously manufacture creams and to investigate whether in- and on-line measurement of viscosity, changes in the concentration of active pharmaceutical ingredient (API), and pH could be used to support optimization of a model cream product. Additionally, the torque of the mixers was assessed for determination of the physical properties of the cream. Two Raman probes with different probe optics were compared for characterization of the API concentration. The API concentration, amount of neutralizer, and mixing speed of the CM line were systematically varied. Both the PhAT probe with a larger sampling volume and immersion Raman probe with a smaller sampling volume could detect the step changes in the API concentration. The torque from the mixer was compared with the viscosity measurements, but the torque signal could not be correlated with the viscosity due to the dynamic nature of the polymer conformation and the time-dependency of this property. Adjustment of pH of the cream could be monitored with the current installation. The investigated PAT tools could be implemented into a continuous line and, further, be used to support the optimization of a model cream composition and related process parameters.

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References

  1. Mahalingam R, Li X, Jasti, BR. Semisolid Dosages: Ointments, Creams, and Gels. In, S. C. Gad, editor. Pharmaceutical Sciences Encyclopedia. 2010. p. 267–312. https://doi.org/10.1002/9780470571224.pse348.

  2. Burcham CL, Florence AJ, Johnson MD. Continuous manufacturing in pharmaceutical process development and manufacturing. Annu Rev Chem Biomol Eng. 2018;9(1):253–81. https://doi.org/10.1146/annurev-chembioeng-060817-084355.

    Article  PubMed  Google Scholar 

  3. Matsunami K, Miyano T, Arai H, Nakagawa H, Hirao M, Sugiyama H. Decision support method for the choice between batch and continuous technologies in solid drug product manufacturing. Ind Eng Chem Res. 2018;57(30):9798–809. https://doi.org/10.1021/acs.iecr.7b05230.

    Article  CAS  Google Scholar 

  4. Steiner R, Jornitz M. Continuous processing in the pharmaceutical industry: status and perspective. In: Kleinebudde P, Khinast J, Rantanen J, editors. Continuous Manufacturing of Pharmaceuticals. 2017. p. 369–403. https://doi.org/10.1002/9781119001348.ch11

  5. Helal NA, Elnoweam O, Eassa HA, Amer AM, Eltokhy MA, Helal MA, et al. Integrated continuous manufacturing in pharmaceutical industry: current evolutionary steps toward revolutionary future. Pharmaceutical Patent Analyst. 2019;8(4):139–61. https://doi.org/10.4155/ppa-2019-0011.

    Article  CAS  PubMed  Google Scholar 

  6. FDA, 2019. U.S. Food and Drug Administration (FDA) Guidance for Industry: Quality Considerations for Continuous Manufacturing Guidance for Industry, Rockville, MD, Feb 2019.

  7. Driessen FM, Ubbels J, Stadhouders J. Continuous manufacture of yogurt. II. Procedure and apparatus for continuous coagulation. Biotechnol Bioeng. 1977;19(6):841–51. https://doi.org/10.1002/bit.260190605.

    Article  CAS  Google Scholar 

  8. Divone P. Semi-continuous manufacturing of personal care liquids. 2013. http://www.engconf.org/staging/wp-content/uploads/2013/12/Divone-UnileverICB-13AQ-Sunday.pdf. Accessed 10 Oct 2019.

  9. Akhtar M, Murray BS, Dowu S. A novel continuous process for making mayonnaise and salad cream using the spinning disc reactor: Effect of heat treatment. Food Hydrocoll. 2014;42:223–8. https://doi.org/10.1016/j.foodhyd.2014.06.007.

    Article  CAS  Google Scholar 

  10. Bhagurkar AM, Angamuthu M, Patil H, Tiwari RV, Maurya A, Hashemnejad SM, et al. Development of an ointment formulation using hot-melt extrusion technology. AAPS PharmSciTech. 2016;17(1):158–66. https://doi.org/10.1208/s12249-015-0453-3.

    Article  CAS  PubMed  Google Scholar 

  11. Pawar J, Narkhede R, Amin P, Tawde V. Design and evaluation of topical diclofenac sodium gel using hot melt extrusion technology as a continuous manufacturing process with Kolliphor® P407. AAPS PharmSciTech. 2017;18(6):2303–15. https://doi.org/10.1208/s12249-017-0713-5.

    Article  CAS  PubMed  Google Scholar 

  12. Bostijn N, Van Renterghem J, Dhondt W, Vervaet C, De Beer T. A continuous manufacturing concept for a pharmaceutical oral suspension. Eur J Pharm Sci. 2018;123:576–83. https://doi.org/10.1016/j.ejps.2018.08.015.

    Article  CAS  PubMed  Google Scholar 

  13. ICH. Pharmaceutical Development Q8(R2) step 4 version, ICH harmonized tripartite guidelines. In International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use. 2009.

  14. Sivaraman A, Banga A. Quality by design approaches for topical dermatological dosage forms. Research and Reports in Transdermal Drug Delivery. 2015;9. https://doi.org/10.2147/RRTD.S82739.

  15. Simões A, Veiga F, Vitorino C, Figueiras A. A tutorial for developing a topical cream formulation based on the quality by design approach. J Pharm Sci. 2018;107(10):2653–62.

    Article  Google Scholar 

  16. Qwist PK, Sander C, Okkels F, Jessen V, Baldursdottir S, Rantanen J. On-line rheological characterization of semi-solid formulations. Eur J Pharm Sci. 2019;128:36–42. https://doi.org/10.1016/j.ejps.2018.11.014.

    Article  CAS  PubMed  Google Scholar 

  17. Verstraeten M, Van Hauwermeiren D, Hellings M, Hermans E, Geens J, Vervaet C, et al. Model-based NIR spectroscopy implementation for in-line assay monitoring during a pharmaceutical suspension manufacturing process. Int J Pharm. 2018;546(1–2):247–54. https://doi.org/10.1016/j.ijpharm.2018.05.043.

    Article  CAS  PubMed  Google Scholar 

  18. Bostijn N, Dhondt W, Vervaet C, De Beer T. PAT-based batch statistical process control of a manufacturing process for a pharmaceutical ointment. Eur J Pharm Sci. 2019b:136.

  19. Bostijn N, Hellings M, Van Der Veen M, Vervaet C, De Beer T. In-line UV spectroscopy for the quantification of low-dose active ingredients during the manufacturing of pharmaceutical semi-solid and liquid formulations. Anal Chim Acta. 2018a;1013:54–62.

    Article  CAS  Google Scholar 

  20. Islam MT, Rodríguez-Hornedo N, Ciotti S, Ackermann C. The potential of Raman spectroscopy as a process analytical technique during formulations of topical gels and emulsions. Pharm Res. 2004;21(10):1844–51.

    Article  CAS  Google Scholar 

  21. De Beer TRM, Baeyens WRG, Ouyang J, Vervaet C, Remon JP. Raman spectroscopy as a process analytical technology tool for the understanding and the quantitative in-line monitoring of the homogenization process of a pharmaceutical suspension. Analyst. 2006;131(10):1137–44.

    Article  Google Scholar 

  22. Pu Y, Medendorp JP, Yonzon CR. Real-time monitoring of active ingredient dispersion in a pharmaceutical aqueous suspension using Raman spectroscopy. J Raman Spectrosc. 2011;42(11):1994–9.

    Article  CAS  Google Scholar 

  23. Tegeli V, Thorat YS, Shivsharan U, Gajeli GB, Kumbhar ST, Chougule GK. Pemulen as a versatile emulsifier. Int J Drug Form Res. 2011;2:52–63.

    Google Scholar 

  24. Rao M. Measurement of flow and viscoelastic properties. In: Rheology of Fluid, Semisolid, and Solid Foods. Food Engineering Series. Springer, Boston, 2014, MA. p. 63–159. https://doi.org/10.1007/978-1-4614-9230-6_3

  25. Choplin L, Torandell S, Servoin J. In situ rheological monitoring in semi-batch emulsification process for cosmetic lotion production. Can J Chem Eng. 1998;76(3):506–10.

    Article  CAS  Google Scholar 

  26. Faure A, York P, Rowe RC. Process control and scale-up of pharmaceutical wet granulation processes: a review. Eur J Pharm Biopharm. 2001;52(3):269–77. https://doi.org/10.1016/s0939-6411(01)00184-9.

    Article  CAS  PubMed  Google Scholar 

  27. Bostijn N, Van Renterghem J, Vanbillemont B, Dhondt W, Vervaet C, De Beer T. Continuous manufacturing of a pharmaceutical cream: investigating continuous powder dispersing and residence time distribution (RTD). Eur J Pharm Sci. 2019;132:106–17.

    Article  CAS  Google Scholar 

  28. Mazurek S, Szostak R. Quantitative analysis of topical gels and ointments by FT-Raman spectroscopy. Vib Spectrosc. 2016;83:1–7. https://doi.org/10.1016/j.vibspec.2015.12.005.

    Article  CAS  Google Scholar 

  29. Rantanen J, Wikstrom H, Rhea FE, Taylor LS. Improved understanding of factors contributing to quantification of anhydrate/hydrate powder mixtures. Appl Spectrosc. 2005;59(7):942–51.

    Article  CAS  Google Scholar 

  30. Park SC, Kim M, Noh J, Chung H, Woo Y, Lee J, et al. Reliable and fast quantitative analysis of active ingredient in pharmaceutical suspension using Raman spectroscopy. Anal Chim Acta. 2007;593(1):46–53.

    Article  CAS  Google Scholar 

  31. Schümann H, Khatibi M, Tutkun MH, Pettersen B, Yang Z, Nydal OJ. Droplet size measurements in oil–water dispersions: a comparison study using FBRM and PVM. J Dispers Sci Technol. 2015;36(10):1432–43.

    Article  Google Scholar 

  32. Jokela P, Fletcher PDI, Aveyard R, Lu J-R. The use of computerized microscopic image analysis to determine emulsion droplet size distributions. J Colloid Interface Sci. 1990;134(2):417–26.

    Article  CAS  Google Scholar 

  33. EDQM. European Directorate for the Quality of Medicines and HealthCare 5.28. Multivariate Statiscal Process Control PA/PH/Exp. VSADM/T (18) 6 ANP. Pharmeuropa (31.3). 2018.

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Acknowledgments

We would like to acknowledge Lubrizol for providing the polymers and Fluidan ApS, Kongens Lyngby, Denmark, for providing the RheoStream® and for technical support.

Funding

Innovation Fund Denmark (grant number 5189-00194B) is acknowledged for partial funding of the PhD project of P. K. Qwist.

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Authors and Affiliations

  1. Department of Pharmacy, University of Copenhagen, Copenhagen, Denmark

    Pernille Kjærgaard Qwist & Jukka Rantanen

  2. Late Stage Product Development, LEO Pharma, Ballerup, Denmark

    Pernille Kjærgaard Qwist, Camilla Sander & Vibeke Jessen

  3. Laboratory of Pharmaceutical Process Analytical Technology, Ghent University, Ghent, Belgium

    Nils Bostijn & Thomas De Beer

  4. UCB Pharma S.A, Brussels, Belgium

    Nils Bostijn

Authors
  1. Pernille Kjærgaard Qwist
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  2. Camilla Sander
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  3. Nils Bostijn
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  4. Vibeke Jessen
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  5. Jukka Rantanen
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  6. Thomas De Beer
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Corresponding author

Correspondence to Thomas De Beer.

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Conflict of Interest

Pernille Kjærgaard Qwist, Camilla Sander, and Vibeke Jessen are employed by the LEO Pharma. Jukka Rantanen and Thomas de Beer have not received any consulting fees from the LEO Pharma.

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Qwist, P.K., Sander, C., Bostijn, N. et al. Continuous Manufacturing of a Polymer Stabilized Emulsion Monitored with Process Analytical Technology. AAPS PharmSciTech 21, 154 (2020). https://doi.org/10.1208/s12249-020-01704-1

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