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Development of Inline Near-Infrared Spectroscopy Method for Real-Time Monitoring of Blend Uniformity of Direct Compression and Granulation-Based Products at Commercial Scales

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Abstract

Blending is a critical intermediate unit operation for all solid oral formulations. For blend uniformity testing, API content in the blend must be quantified precisely. A detailed study was conducted to demonstrate the suitability of inline NIR (near-infrared) spectroscopy for blend uniformity testing of two solid oral formulations: existing direct compression (DC) product with a multistep blending process and granulation-based product with API granules. Both qualitative and quantitative methods were developed at a laboratory scale using statistical moving block standard deviation (MBSD) and multivariate data analysis such as principal component analysis (PCA) and partial least squares (PLS) regression. The qualitative MBSD method demonstrated that there was no need for multiple steps for the existing DC product. Hence, a simplified single-step process was developed for blending. Quantitative PLS models for blending processes of both the products were developed, validated, and successfully implemented at a commercial scale for the real-time release of blends. Results obtained from the validated model were in good agreement with the current method of sampling and chromatography.

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References

  1. ICH harmonized tripartite guideline, Pharmaceutical Development Q8 (R2), 2009. https://database.ich.org/sites/default/files/Q8%28R2%29Guideline.pdf.

  2. US Food and Drug Administration, Guidance for industry, PAT-A framework for innovative pharmaceutical development, manufacturing and quality assurance, 2004. http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm070305.pdf.

  3. Zhong L, Gao L, Li L, Zang H. Trends-process analytical technology in solid oral dosage manufacturing. Eur J Pharm Biopharm. 2020;153:187–99. https://doi.org/10.1016/j.ejpb.2013.01.016.

    Article  CAS  PubMed  Google Scholar 

  4. Laske S, Paudel A, Scheibelhofer O. A review of PAT strategies in secondary solid oral dosage manufacturing of small molecules. J Pharm Sci. 2017;106(3):667–712. https://doi.org/10.1016/j.xphs.2016.11.011.

    Article  CAS  PubMed  Google Scholar 

  5. Wahl P, Fruhmann G, Sacher S, Straka G, Sowinski S, Khinast J. PAT for tableting: inline monitoring of API and excipients via NIR spectroscopy. Eur J Pharm Biopharm. 2014;87(2):271–8. https://doi.org/10.1016/j.ejpb.2014.03.021.

    Article  CAS  PubMed  Google Scholar 

  6. Fonteyne M, Vercruysse J, De Leersnyder F, Van Snick B, Vervaet C, Remon J, De Beer T. Process analytical technology for continuous manufacturing of solid-dosage forms. Trends Anal Chem. 2015;67:159–66. https://doi.org/10.1016/j.trac.2015.01.011.

    Article  CAS  Google Scholar 

  7. Riolo D, Piazza A, Cottini C, Serafini M, Lutero E, Cuoghi E, et al. Raman spectroscopy as a PAT for pharmaceutical blending: advantages and disadvantages. J Pharm Biomed Anal. 2018;149:329–34. https://doi.org/10.1016/j.jpba.2017.11.030.

    Article  CAS  PubMed  Google Scholar 

  8. Rantanen J. Process analytical applications of Raman spectroscopy. J Pharm Pharmacol. 2007;59:171–7. https://doi.org/10.1211/jpp.59.2.0004.

    Article  CAS  PubMed  Google Scholar 

  9. 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. 2011;417:32–47. https://doi.org/10.1016/j.ijpharm.2010.12.012.

    Article  CAS  PubMed  Google Scholar 

  10. Taday P. Applications of terahertz spectroscopy to pharmaceutical sciences. Philos Trans A Math Phys Eng Sci. 1815;2004(362):351–63. https://doi.org/10.1098/rsta.2003.1321.

    Google Scholar 

  11. Ajito K. Terahertz spectroscopy for pharmaceutical and biomedical applications. IEEE Transactions on Tetrahertz Sci and Tech. 2015;5(6):1140.

    CAS  Google Scholar 

  12. Guay JM, Lapointe-Garant PP, Gosselin R, Simard JS, Abatzoglou N. Development of a multivariate light-induced fluorescence (LIF) PAT tool for in-line quantitative analysis of pharmaceutical granules in a V-blender. Eur J Pharm Biopharm. 2014;86:524–31. https://doi.org/10.1016/j.ejpb.2013.12.013.

    Article  CAS  PubMed  Google Scholar 

  13. Lin H, Zhang Z, Markl D, Zeitler J, Shen Y. A review of the applications of OCT for analysing pharmaceutical film coatings. Appl Sci. 2018;8:2700. https://doi.org/10.3390/app8122700.

    Article  CAS  Google Scholar 

  14. Barton F. Theory and principles of near infrared spectroscopy. Spectrosc Eur. 2002;14(1):12–8.

    Google Scholar 

  15. Roggo Y, Chalus P, Maurer L, Lema-Martinez C, Edmond A, Jent N. A review of near infrared spectroscopy and chemometrics in pharmaceutical technologies. J Pharm Biomed Anal. 2007;44(3):683–700. https://doi.org/10.1016/j.jpba.2007.03.023.

    Article  CAS  PubMed  Google Scholar 

  16. Yu L, Amidon G, Khan M, Hoag S, Polli J, Raju G, Woodcock J. Understanding pharmaceutical quality by design. The AAPS Journal. 2014; 16(4):771–783. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4070262/

  17. Muzzio F, Robinson P, Wightman C, Dean B. Sampling practices in powder blending. Int J Pharm. 1997;155:153–78. https://doi.org/10.1016/S0378-5173(97)04865-5.

    Article  CAS  Google Scholar 

  18. Berman J. The compliance and science of blend uniformity analysis. PDA J Pharm Sci Technol. 2001;55(4):209–22.

    CAS  PubMed  Google Scholar 

  19. Boehm G, Clark J, Dietrick J, Foust L, Garcia T, Gavini M, Gelber L, Goeffroy JM, Jimenez P, Mergen G, Muzzio F, Planchard J, Prescott J, Timmermans J, Takiar N. The use of stratified sampling of blend and dosage units to demonstrate adequacy of mix for powder blends. PDA J Pharm Sci Tech. 2003;57(2):59–74.

    Google Scholar 

  20. Muzzio F, Goodridge C, Alexander A, Arratia P, Yang H, Sudah O, Mergen G. Sampling and characterization of pharmaceutical powders and granular blends. Int J Pharm. 2003;250:51–64. https://doi.org/10.1016/S0378-5173(02)00481-7.

    Article  CAS  PubMed  Google Scholar 

  21. US Food and Drug Administration, Guidance for industry, development and submission of near infrared analytical procedures, 2021.https://www.fda.gov/media/91343/download

  22. Abatzoglou N, Lapointe-Garant P, Simard J. Real-time NIR monitoring of pharmaceutical blending processes with multivariate quantitative models. Eur Pharmacol Rev. 2009;5:57–67.

    Google Scholar 

  23. Berntsson O, Danielsson L, Lagerholm B, Folestad S. Quantitative in-line monitoring of powder blending by near infrared reflection spectroscopy. Powder Technol. 2002;123:185–93. https://doi.org/10.1016/S0032-5910(01)00456-9.

    Article  CAS  Google Scholar 

  24. Igne B, Juan A, Jaumot J, Lallemand J, Preys S, Drennen J, Anderson CA. Modeling strategies for pharmaceutical blend monitoring and end-point determination by near-infrared spectroscopy. Int J Pharm. 2014;473:219–31. https://doi.org/10.1016/j.ijpharm.2014.06.061.

    Article  CAS  PubMed  Google Scholar 

  25. Rajalahti T, Kvalheim O. Multivariate data analysis in pharmaceutics: a tutorial review. Int J Pharm. 2011;417(1–2):280–90. https://doi.org/10.1016/j.ijpharm.2011.02.019.

    Article  CAS  PubMed  Google Scholar 

  26. Ferreira A, Tobyn M. Multivariate analysis in the pharmaceutical industry: enabling process understanding and improvement in the PAT and QbD era. Pharm Dev Technol. 2015;20(5):513–27. https://doi.org/10.3109/10837450.2014.898656.

    Article  CAS  PubMed  Google Scholar 

  27. Sekulic SS, Wakeman J, Doherty P, Hailey P. Automated system for the on-line monitoring of powder blending processes using near-infrared spectroscopy. Part II. Qualitative approaches to blend evaluation. J Pharm Biomed Anal. 1998;17(8):1285–309. https://doi.org/10.1016/S0731-7085(98)00025-9.

    Article  CAS  PubMed  Google Scholar 

  28. Besseling R, Damen M, Tran T, Nguyen T, Dries K, Oostra W, Gerich A. An efficient, maintenance free and approved method for spectroscopic control and monitoring of blend uniformity: the moving F-test. J Pharm Biomed Anal. 2015;114:471–81. https://doi.org/10.1016/j.jpba.2015.06.019.

    Article  CAS  PubMed  Google Scholar 

  29. Wargo D, Drennen J. Near-infrared spectroscopic characterization of pharmaceutical powder blends. J Pharm Biomed Anal. 1996;14(11):1415–23. https://doi.org/10.1016/0731-7085(96)01739-6.

    Article  CAS  PubMed  Google Scholar 

  30. Blanco M, Bañó RG, Bertran E. Monitoring powder blending in pharmaceutical processes by use of near infrared spectroscopy. Talanta. 2002;56(1):203–12. https://doi.org/10.1016/S0039-9140(01)00559-8.

    Article  CAS  PubMed  Google Scholar 

  31. Sánchez FC, Toft J, Bogaert B, Massart D, Dive S, Hailey P. Monitoring powder blending by NIR spectroscopy. Fresenius J Anal Chem. 1995;352:771–8. https://doi.org/10.1007/BF00323062.

    Article  Google Scholar 

  32. Puchert T, Holzhauer C, Menezes J, Lochmann D, Reich G. A new PAT/QbD approach for the determination of blend homogeneity: combination of online NIRS analysis with PC scores distance analysis (PC-SDA). Eur J Pharm Biopharm. 2011;78(1):173–82. https://doi.org/10.1016/j.ejpb.2010.12.015.

    Article  CAS  PubMed  Google Scholar 

  33. Plugge W, Vlies C. Near-infrared spectroscopy as an alternative to assess compliance of ampicillin trihydrate with compendial specifications. J Pharm Biomed Anal. 1993;11:435–42. https://doi.org/10.1016/0731-7085(93)80154-S.

    Article  CAS  PubMed  Google Scholar 

  34. Storme-Paris I, Clarot I, Esposito S, Chaumeil J, Nicolas A, Brion F, et al. Near infrared spectroscopy homogeneity evaluation of complex powder blends in a small-scale pharmaceutical preformulation process, a real-life application. Eur J Pharm Biopharm. 2009;72:189–98. https://doi.org/10.1016/j.ejpb.2008.11.002.

    Article  CAS  PubMed  Google Scholar 

  35. Beer T, Bodson C, Dejaegher B, Walczak B, Vercruysse P, Burggraeve A, et al. Raman spectroscopy as a process analytical technology (PAT) tool for the in-line monitoring and understanding of a powder blending process. J Pharm Biomed Anal. 2008;48:772–9. https://doi.org/10.1016/j.jpba.2008.07.023.

    Article  CAS  PubMed  Google Scholar 

  36. El-Hagrasy AS, Delgado-Lopez M, Drennen JK. A process analytical technology approach to near-infrared process control of pharmaceutical powder blending: Part II: qualitative near-infrared models for prediction of blend homogeneity. J Pharm Sci. 2006;95:407–21. https://doi.org/10.1002/jps.20466.

    Article  CAS  PubMed  Google Scholar 

  37. Gerich A, Verhoog J, Damen M, Verhoeven W, Chamarthy S, Besseling R. Detection of lumps in powder blends by inline NIR, Pharmaceutical Technology, Pharmaceutical Technology. 2017; 41(9): 36–44. https://www.pharmtech.com/view/detection-lumps-powder-blends-inline-nir

  38. Wu H, Tawakkul M, White M, Khan M. Quality-by-design (QbD): an integrated multivariate approach for the component quantification in powder blends. Int J Pharm. 2009;372:39–48. https://doi.org/10.1016/j.ijpharm.2009.01.002.

    Article  CAS  PubMed  Google Scholar 

  39. Chavez PZ, Sacré PY, De Bleye C, Netchacovitch L, Mantanus J, Motte H, Schubert M, Hubert P, Ziemons E. Active content determination of pharmaceutical tablets using near infrared spectroscopy as process analytical technology tool. Talanta. 2015;144:1352–9. https://doi.org/10.1016/j.talanta.2015.08.018.

    Article  CAS  PubMed  Google Scholar 

  40. Nakagawa H, Kano M, Hasebe S, Miyano T, Watanabe T, Wakiyama N. Verification of model development technique for NIR-based real-time monitoring of ingredient concentration during blending. Int J Pharm. 2014;471:264–75. https://doi.org/10.1016/j.ijpharm.2014.05.013.

    Article  CAS  PubMed  Google Scholar 

  41. Jaumot J, Igne B, Anderson C, Drennen J, de Juan A. Blending process modeling and control by multivariate curve resolution. Talanta. 2013;117:492–504. https://doi.org/10.1016/j.talanta.2013.09.037.

    Article  CAS  PubMed  Google Scholar 

  42. Martínez L, Peinadob A, Liesum L. In-line quantification of two active ingredients in a batch blending process by near-infrared spectroscopy: influence of physical presentation of the sample. Int J Pharm. 2013;451:67–75. https://doi.org/10.1016/j.ijpharm.2013.04.078.

    Article  CAS  PubMed  Google Scholar 

  43. Alam MA, Liu Y. An agile and robust in-line NIR potency deviation detection method for monitoring and control of a continuous direct compression process. Int J Pharm. 2021;601:120521. https://doi.org/10.1016/j.ijpharm.2021.12052.

    Article  CAS  PubMed  Google Scholar 

  44. Mohan S, Momose W, Katz J, Hossain MN, Velez N, Drennen J, Anderson C. A robust quantitative near infrared modeling approach for blend monitoring. J Pharm Biomed Anal. 2018;148:51–7. https://doi.org/10.1016/j.jpba.2017.09.011.

    Article  CAS  PubMed  Google Scholar 

  45. Rinnan A, van den Berg F, Engelsen S. Review of the most common pre-processing techniques for near-infrared spectra. Trends Anal Chem. 2009;28(10):1201–22. https://doi.org/10.1016/j.trac.2009.07.007.

    Article  CAS  Google Scholar 

  46. Barnes R, Dhanoa M, Lister S. Standard normal variate transformation and de-trending of near–infrared diffuse reflectance spectra. Appl Spectrosc. 1989;43(5):772–7. https://doi.org/10.1366/0003702894202201.

    Article  CAS  Google Scholar 

  47. Mark H, Workman J. Derivatives in spectroscopy. Spectrosc. 2003;18(4):37.

    Google Scholar 

  48. Cowe I, McNicol J. The use of principal components in the analysis of near-infrared spectra. Appl. Spectrosc. 1985; 39: 257–266. https://opg.optica.org/as/abstract.cfm?URI=as-39-2-257

  49. Wold S, Esbensen K, Geladi P. Principal component analysis. Chemom Intell Lab Syst. 1987;2:37–52. https://doi.org/10.1016/0169-7439(87)80084-9.

    Article  CAS  Google Scholar 

  50. Gerlach R, Kowalski B, Wold H. Partial least-squares path modelling with latent variables. Anal Chim Acta. 1979;112(4):417–21. https://doi.org/10.1016/S0003-2670(01)85039-X.

    Article  CAS  Google Scholar 

  51. Wold S, Sjostrom M, Eriksson L. PLS-regression: a basic tool of chemometrics. Chemom Intell Lab Syst. 2001;58:109–30. https://doi.org/10.1016/S0169-7439(01)00155-1.

    Article  CAS  Google Scholar 

  52. De Bleye C, Chavez P, Mantanus J, Marini R, Hubert P, Rozet E, Ziemons E. Critical review of near-infrared spectroscopic methods validations in pharmaceutical applications. J Pharm Biomed Anal. 2012;69:125–32. https://doi.org/10.1016/j.jpba.2012.02.003.

    Article  CAS  PubMed  Google Scholar 

  53. US Food and Drug Association Draft guideline-powder blends and finished dosage units — stratified in-process dosage unit sampling and assessment 2003. https://pqri.org/wp-content/uploads/2015/12/FDADraftGuide.pdf

  54. Brone D, Muzzio F. Enhanced mixing in double-cone blenders. Powder Technol. 2000;110:179–89. https://doi.org/10.1016/S0032-5910(99)00204-1.

    Article  CAS  Google Scholar 

  55. Barling D, Morton D, Hapgood K. Pharmaceutical dry powder blending and scale-up: maintaining equivalent mixing conditions using a coloured tracer powder. Powder Technol. 2015;270:461–9. https://doi.org/10.1016/j.powtec.2014.04.069.

    Article  CAS  Google Scholar 

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Acknowledgements

The authors are thankful to the manufacturing team for helping in performing the trials.

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Authors and Affiliations

  1. QbD Department, Integrated Product Development, Cipla Ltd., Maharashtra, Mumbai, India

    Aruna Khanolkar, Bhaskar Patil, Viraj Thorat & Gautam Samanta

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  1. Aruna Khanolkar
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  2. Bhaskar Patil
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Contributions

Aruna Khanolkar designed the experiments, interpreted the analysis, supervised the project, and modified the manuscript. Bhaskar Patil performed the experiments, analyzed the spectra data, and wrote the original manuscript. Viraj Thorat performed the experiments and analyzed the experimental spectral data. Gautam Samanta was responsible for supervision, review, and editing of the manuscript.

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Correspondence to Gautam Samanta.

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Khanolkar, A., Patil, B., Thorat, V. et al. Development of Inline Near-Infrared Spectroscopy Method for Real-Time Monitoring of Blend Uniformity of Direct Compression and Granulation-Based Products at Commercial Scales. AAPS PharmSciTech 23, 235 (2022). https://doi.org/10.1208/s12249-022-02392-9

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