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Journal of Pharmaceutical Innovation

, Volume 3, Issue 4, pp 258–270 | Cite as

Quality by Design Methodology for Development and Scale-up of Batch Mixing Processes

  • Patricia M. Portillo
  • Marianthi Ierapetritou
  • Silvina Tomassone
  • Christine Mc Dade
  • Donald Clancy
  • Petrus P. C. Avontuur
  • Fernando J. Muzzio
Research Article

Abstract

In this study, a quality by design approach was applied to the design and scale-up of a batch mixing process. Mixtures of acetaminophen and lactose were sampled at different mixing times using a groove sampler. Samples were subsequently analyzed using NIR reflection spectroscopy. The effects of four processing parameters on the empirical mixing rate in a bin blender were examined. Blender rotation rate (two levels), powder fill level (two levels), powder cohesion (two levels), and blender size (three levels) represent the four parameters studied. Blender geometry and blender loading method were treated as constant parameters. Statistical analysis was used to assess the impact each parameter had on the mixing rate. Blender size (p = 0.02), powder cohesion (p = 0.05), and rotation rate (p = 0.07) all significantly affected the mixing rate. The least significant parameter was the vessel fill level (p = 0.18), indicating mixing performance is not strongly affected by fill level, given the range studied.

Keywords

Quality by design Batch powder mixing Bin blender Statistical analysis Mixing rate 

References

  1. 1.
    Mehrotra A, Chaudhuri B, Faqih A, Tomassone MS, Muzzio FJ. A modeling approach for understanding effects of powder flow properties on tablet weight variability. Powder Technol. 2008. doi: 10.1016/j.powtec.2008.05.016 (in press).
  2. 2.
    James MN. Design, manufacture and materials; their interaction and role in engineering failures. Eng Fail Anal 2005;12:662–78.CrossRefGoogle Scholar
  3. 3.
    Alexander AW, Muzzio FJ. Batch size increase in dry blending and mixing. In: Levin M, editor. Pharmaceutical process scale-up. New York: Marcel Dekker; 2001.Google Scholar
  4. 4.
    Hassanpour A, Antony SJ, Ghadiria M. Effect of size ratio on the behaviour of agglomerates embedded in a bed of particles subjected to shearing: DEM analysis. Chem Eng Sci 2007;62(4):935–42.CrossRefGoogle Scholar
  5. 5.
    Llusa M, Muzzio F. The effect of shear mixing on the blending of cohesive lubricants and drugs, Pharmaceutical Technology, http://pharmtech.findpharma.com/pharmtech/Mixing+and+blending/The-Effect-of-Shear-Mixing-on-the-Blending-of-Cohe/ArticleStandard/Article/detail/283906. Accessed 1 Oct 2008; 2005.
  6. 6.
    Arratia PE, Duong N-H, Muzzio FJ, Godbole P, Lange A, Reynolds S. Characterizing mixing and lubrication in the Bohle Bin blender. Powder Technol 2006;161:202–8.CrossRefGoogle Scholar
  7. 7.
    Alexander A, Shinbrot T, Muzzio FJ. Granular segregation in the double-cone blender: transitions and mechanisms. Phys Fluids 2001;13(3):579–87.CrossRefGoogle Scholar
  8. 8.
    Alexander A, Shinbrot T, Muzzio FJ. Segregation patterns in V-blenders. Chem Eng Sci 2003;58:487–96.CrossRefGoogle Scholar
  9. 9.
    Sudah OS, Coffin-Beach D, Muzzio FJ. Quantitative characterization of mixing of free-flowing granular material in tote (bin)-blenders. Powder Technol 2002a;126:191–200.CrossRefGoogle Scholar
  10. 10.
    Alexander A, Arratia P, Goodridge C, Sudah O, Brone D, Muzzio F. Characterization of the performance of bin blenders. Part 3: cohesive powders. Pharm Tech 2004;28:54–74.Google Scholar
  11. 11.
    Muzzio FJ, Alexander A, Goodridge C, Shen E, Shinbrot T. Solid mixing. In: Paul EL, Atiemo-Obeng VA, Suzanne K, editors. Chapter 15A, handbook of industrial mixing: science and practice. New York: Wiley; 2004. p. 887–923.Google Scholar
  12. 12.
    Brone D, Alexander A, Muzzio FJ. Quantitative characterization of mixing of dry powders in V-blenders. AlChE J 1998;44(2):271–8.Google Scholar
  13. 13.
    Sudah OS, Coffin-Beach D, Muzzio FJ. Effects of blender rotation speed and discharge on the homogeneity of cohesive and free-flowing mixtures. Int J Pharm 2002b;247:57–68.PubMedCrossRefGoogle Scholar
  14. 14.
    FDA. Powder blends and finished dosage units—stratified in process dosage unit sampling and assessment, Pharmaceutical CGMP’s, Guidance for Industry; 2003.Google Scholar
  15. 15.
    International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use, ICH Harmonised Tripartite Guideline, Pharmaceutical Development Q8(R1), 1-November-2007.Google Scholar
  16. 16.
    International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use, ICH Harmonised Tripartite Guideline, Quality Risk Management Q9, Step 4, 9-November-2005.Google Scholar
  17. 17.
    International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use, ICH Harmonised Tripartite Guideline, Pharmaceutical Quality System Q10, Step 4, 4-June-2008.Google Scholar
  18. 18.
    Cogdill RP, Drennen JK. Risk-based quality by design (QbD): a Taguchi perspective on the assessment of product quality, and the quantitative linkage of drug product parameters and clinical performance. J Pharm Innov 2008;3(1):23–29.CrossRefGoogle Scholar
  19. 19.
    Lemieux M, Bertrand F, Chaouki J, Gosselin P. Comparative study of the mixing of free-flowing particles in a V-blender and a bin-blender. Chem Eng Sci 2007;62(6):1783–802.CrossRefGoogle Scholar
  20. 20.
    Muguruma Y, Tanaka T, Kawatake S, Tsuji Y. Discrete particle simulation of a rotary vessel mixer with baffles. Powder Technol 1997;93(3):261–66.CrossRefGoogle Scholar
  21. 21.
    Muzzio FJ, Robinson P, Wightman C, Brone D. Sampling practices in powder blending. Int J Pharm 1997;155(2):153–78.CrossRefGoogle Scholar
  22. 22.
    Duong N-H, Arratia PE, Muzzio FJ, Lange A, Timmermans J, Reynolds S. Homogeneity study using NIR spectroscopy: tracking magnesium stearate in Bohle Bin-blenders. Drug Dev Ind Pharm 2003;29:679–87.PubMedCrossRefGoogle Scholar
  23. 23.
    Alexander A, Goodridge C, Muzzio F, Arratia P, Brone D, Sudah O. Part 1. Pharm Tech. 2004.Google Scholar
  24. 24.
    Brone D, Muzzio FJ. Enhanced mixing in double-cone blenders. Powder Technol 2000;110:179–89.CrossRefGoogle Scholar
  25. 25.
    Manjunath K, Dhodapkar S, Jacob K. Solid mixing: mixing of pariculate solids in the process industries. In: Paul EL, Atiemo-Obeng VA, Suzanne K, editors. Chapter 15B, handbook of industrial mixing: science and practice. New York: Wiley; 2004. p. 887–923.Google Scholar
  26. 26.
    Portillo P, Muzzio F, Ierapetritou MG. Characterizing powder mixing processes utilizing compartment models. Int J Pharm 2006;320:14–22.PubMedCrossRefGoogle Scholar
  27. 27.
    Schwedes J. Review of testers for measuring flow properties of bulk solids. Granul Matter 2003;5:1–43.CrossRefGoogle Scholar
  28. 28.
    Walton OR, De Moor CP, Gill KS. Effects of gravity on cohesive behavior of fine powders: implications for processing Lunar regolith. Granul Matter 2007;9:353–63.CrossRefGoogle Scholar
  29. 29.
    Chaudhuri B, Mehrotra A, Muzzio FJ, Tomassone MS. Cohesive effects in powder mixing in a tumbling blender. Powder Technol 2006;165:105–14.CrossRefGoogle Scholar
  30. 30.
    Chang R-K, Badawy S, Hussain MA, Buehler JD. Drug development and industrial pharmacy. Drug Dev Ind Pharm 1995;21(3):361–8.CrossRefGoogle Scholar
  31. 31.
    Li H, McCarthy JJ. Controlling cohesive particle mixing and segregation. Phys Rev Lett 2003;90:184301–4.PubMedCrossRefGoogle Scholar
  32. 32.
    Weber MW, Hrenya CM. Square-well model for cohesion in fluidized beds. Chem Eng Sci 2006;61(14):4511–27.CrossRefGoogle Scholar
  33. 33.
    Stanford MK, DellaCorte C, Eylon D. Particle morphology effects on flow characteristics of PS304 plasma spray coating feedstock powder blend. NASANASA/TM-2002-211206. Springfield, VA: National Technical Information Service; 2002.Google Scholar
  34. 34.
    Sheehan C, United States Pharmacopeia, 1174, powder flow, http://www.pharmacopeia.cn/v29240/usp29nf24s0_c1174.html. Accessed 1 Oct 2008.
  35. 35.
    Faqih A, Chaudhuri B, Alexander A, Davies C, Muzzio FJ, Tomassone MS. An experimental/computational approach for examining unconfined cohesive powder flow. Int J Pharm 2006;324:116–27.PubMedCrossRefGoogle Scholar
  36. 36.
    Dehlert GW. A first course in design and analysis of experiments. New York: Freeman; 2000. p. 48.Google Scholar

Copyright information

© International Society for Pharmaceutical Engineering 2008

Authors and Affiliations

  • Patricia M. Portillo
    • 1
  • Marianthi Ierapetritou
    • 1
  • Silvina Tomassone
    • 1
  • Christine Mc Dade
    • 2
  • Donald Clancy
    • 2
  • Petrus P. C. Avontuur
    • 3
  • Fernando J. Muzzio
    • 1
  1. 1.Department of Chemical and Biochemical EngineeringRutgers UniversityPiscatawayUSA
  2. 2.Process TechnologiesGlaxo Smith Kline CompanyKing of PrussiaUSA
  3. 3.GlaxoSmithKline R&D, New Frontiers Science ParkEssexUK

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