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Acta Pharmaceutica

The Journal of Croatian Pharmaceutical Society

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1846-9558
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Volume 64, Issue 3 (Sep 2014)

Issues

Influence of Process Parameters on Content Uniformity of a Low Dose Active Pharmaceutical Ingredient in a Tablet Formulation According to GMP

Jan Muselík
  • Department of Pharmaceutics Faculty of Pharmacy University of Veterinary and Pharmaceutical Sciences 612 42 Brno, Czech Republic
  • Other articles by this author:
  • De Gruyter OnlineGoogle Scholar
/ Aleš Franc
  • Department of Pharmaceutics Faculty of Pharmacy University of Veterinary and Pharmaceutical Sciences 612 42 Brno, Czech Republic
  • Other articles by this author:
  • De Gruyter OnlineGoogle Scholar
/ Petr Doležel
  • Department of Pharmaceutics Faculty of Pharmacy University of Veterinary and Pharmaceutical Sciences 612 42 Brno, Czech Republic
  • Other articles by this author:
  • De Gruyter OnlineGoogle Scholar
/ Roman Goněc / Anna Krondlová
  • Corresponding author
  • Department of Pharmaceutics Faculty of Pharmacy University of Veterinary and Pharmaceutical Sciences 612 42 Brno, Czech Republic
  • Email
  • Other articles by this author:
  • De Gruyter OnlineGoogle Scholar
/ Ivana Lukášová
  • Department of Pharmaceutics Faculty of Pharmacy University of Veterinary and Pharmaceutical Sciences 612 42 Brno, Czech Republic
  • Other articles by this author:
  • De Gruyter OnlineGoogle Scholar
Published Online: 2014-10-08 | DOI: https://doi.org/10.2478/acph-2014-0022

Abstract

The article describes the development and production of tablets using direct compression of powder mixtures. The aim was to describe the impact of filler particle size and the time of lubricant addition during mixing on content uniformity according to the Good Manufacturing Practice (GMP) process validation requirements. Processes are regulated by complex directives, forcing the producers to validate, using sophisticated methods, the content uniformity of intermediates as well as final products. Cutting down of production time and material, shortening of analyses, and fast and reliable statistic evaluation of results can reduce the final price without affecting product quality. The manufacturing process of directly compressed tablets containing the low dose active pharmaceutical ingredient (API) warfarin, with content uniformity passing validation criteria, is used as a model example. Statistic methods have proved that the manufacturing process is reproducible. Methods suitable for elucidation of various properties of the final blend, e.g., measurement of electrostatic charge by Faraday pail and evaluation of mutual influences of researched variables by partial least square (PLS) regression, were used. Using these methods, it was proved that the filler with higher particle size increased the content uniformity of both blends and the ensuing tablets. Addition of the lubricant, magnesium stearate, during the blending process improved the content uniformity of blends containing the filler with larger particles. This seems to be caused by reduced sampling error due to the suppression of electrostatic charge.

Keywords: content uniformity; warfarin; validation; narrow therapeutic index; Faraday pail; PLS regression

References

  • 1. L. M. Vercaigni and G. G. Zhanel, Clinical significance of bioequivalence and interchangeability of narrow therapeutic range drugs: Focus on warfarins, J. Pharm. PharmSci. 1 (1998) 92-94.Google Scholar

  • 2. A. K. Wittkowsky, Generic warfarin: Implications for patient care, Pharmacotherapy 17 (1997) 640-643; DOI: 10.1002/j.1875-9114.1997.tb03741.x.PubMedCrossrefGoogle Scholar

  • 3. A. Jaffer and L. Bragg, Practical tips for Warfarin dosing and monitoring, Clev. Clin. J. Med. 70 (2003) 361-371; DOI: 10.3949/ccjm.70.4.361.CrossrefGoogle Scholar

  • 4. United States Court of Appeals, Third Circuit. Court decision in re: Warfarin sodium antitrust litigation, 391 F.3d 516, December 2004; https://bulk.resource.org/courts.gov/c/F3/391/391.F3d.516.02-3758.02-3757.02-3755.02-3603.html; access date October 15, 2013.Google Scholar

  • 5. H. Halkin, A. Shapiro, D. Kurnik, R. Loebstein, V. Shalev and E. Kokia, Increased warfarin doses and decreased international normalized ratio response after nationwide generic switching, Clin. Pharmacol. Ther. 74 (2003) 215-221; DOI: 10.1016/S0009-9236(03)00166-8.CrossrefGoogle Scholar

  • 6. C. N. Swenson and G. Fundak, Observational cohort study of switching warfarin sodium products in a managed care organization, Am. J. Health-Syst. Pharm. 57 (2000) 452-455.Google Scholar

  • 7. A. E. Sawoniak, A. F. Shalansky, P. J. Zed and R. Sundreji, Formulary considerations related to warfarin interchangeability, Can. J. Hosp. Pharm. 55 (2002) 215-218.Google Scholar

  • 8. A. Franc, B. Žaludek, R. Goněc, M. Maleček, H. Tkadlečková and A. Petrovičová, Method of Producing Dosage Units of a Solid Drug Form Containing Warfarin Sodium Salts as Active Component, WO Pat. 2005034919 17 October 2003.Google Scholar

  • 9. A. Franc, M. Rabišková and R. Gonĕc, Impregnation: a progressive method in the production of solid dosage forms with low content of poorly soluble drugs, Eur. J. Parent Pharm. Sci. 16 (2011) 85-93.Google Scholar

  • 10. L. Z. Benet and J. E. Goyan, Bioequivalence and narrow therapeutic index drug, Pharmacotherapy 15 (1995) 433-440; DOI: 10.1002/j.1875-9114.1995.tb04379.x.PubMedCrossrefGoogle Scholar

  • 11. The »Barr Laboratories« Court decision, United States District Court for the District of New Jersey, Civil action No. 92-1744, January 2004; http://www.navigategmp.com/pdf/BarrLabs.pdf; access date October 19, 2013.Google Scholar

  • 12. J. Berman, D. E. Elinski, C. R. Gonzales, J. D. Hofer, P. J. Jimenez, J. A. Planchard, R. J. Tlachac and P. F. Vogel, Blend uniformity analysis: Validation and in-process testing. Technical Report No. 25. PDA (Parenteral Drug Association), PDA J. Pharm. Sci. Technol. 51 (1997) S1-99.Google Scholar

  • 13. FDA Guidance for industry, ANDAs: Blend Uniformity Analysis, Draft guidance, August 1999; http://www.fda.gov/OHRMS/DOCKETS/98fr/992635gd.pdf; access date October 19, 2013.Google Scholar

  • 14. FDA Guidance for industry, Powder Blends and Finished Dosage Units - Stratified In-process Dosage Unit Sampling and Assessment, Draft guidance, October 2003; http://www.fda.gov/OHRMS/DOCKETS/98fr/03d-0493-gdl0001.pdf; access date October 19, 2013.Google Scholar

  • 15. FDA Guidance for industry, Powder Blends and Finished Dosage Units - In-process Bend and Dosage Unit Inspection (Sampling and Evaluation) for Content Uniformity, Revised draft guidance, January 2004; http://www.fda.gov/ohrms/dockets/dailys/04/jan04/013004/03D-0493_emc-000003-01.pdf; access date October 19, 2013.Google Scholar

  • 16. FDA reference material, Oral Solid Dosage Forms Pre/post Approval Issues (1/94), Guide to inspections of oral solid dosage forms, pre/post approval issues for development and validation, January 1994. http://www.fda.gov/ICECI/Inspections/InspectionGuides/ucm074928.htm; access date 19 October, 2013.Google Scholar

  • 17. P. Cholayudth, Establishing acceptance limits for probability of passing multiple stage tests in process validation through a process capability approach, J. Valid. Tech. 15 (2009) 77-90.Google Scholar

  • 18. J. S. Bergum and H. Li, Acceptance limits for the new ICH USP 29 content-uniformity test, Pharm. Tech. 31 (2007) 90-100.Google Scholar

  • 19. J. Kushner, Incorporating Turbula mixers into a blending scale-up model for evaluating the effect of magnesium stearate on tablet tensile strength and bulk specific volume, Int. J. Pharm. 429 (2012) 1-11; DOI: 10.1016/j.ijpharm.2012.02.040.CrossrefWeb of ScienceGoogle Scholar

  • 20. J. Zheng, Formulation and Analytical Development for Low-Dose Oral Drug Products, John Wiley & Sons, New Jersey 2009, pp. 169-196.Google Scholar

  • 21. J. Hilden, M. Schrad, J. Kuehne-Willmore and J. Sloan, A first-principles model for prediction of product dose uniformity based on drug substance particle size distribution, J. Pharm. Sci. 101 (2012) 2364-2371; DOI: 10.1002/jps.23130.CrossrefWeb of ScienceGoogle Scholar

  • 22. Y. Pu, M. Mazumder and C. Cooney, Effects of electrostatic charging on pharmaceutical powder blending homogeneity, J. Pharm. Sci. 98 (2009) 2412-2421; DOI: 10.1002/jps.21595.CrossrefWeb of ScienceGoogle Scholar

  • 23. J. Muselík and A. Franc, Evaluation of content uniformity of tablets with a low content of the active ingredient with a narrow therapeutic index, Ces. Slov. Farm. 61 (2012) 271-275.PubMedGoogle Scholar

  • 24. D. M. Taylor, Measuring techniques for electrostatistics, Electrostatics 51-52 (2001) 502-508.CrossrefGoogle Scholar

  • 25. H. Martens and M. Martens, Modified jack-knife estimation of parameter uncertainty in bilinear modeling by partial least squares regression (PLSR), Food Qual. Prefer. 11 (2000) 5-16; DOI: http://dx.doi.org/10.1016/S0950-3293(99)00039-7.CrossrefGoogle Scholar

  • 26. A. Franc, J. Muselík, R. Máslová and J. Hadrabová, Content uniformity of warfarin-containing mixtures and tablets, Ces. Slov. Farm. 62 (2013) 177-181.Google Scholar

  • 27. M. Perrault, F. Bertrand and J. Chaouki, An investigation of magnesium stearate mixing in a Vblender through gamma-ray detection, Powder Technol. 200 (2010) 234-245.Google Scholar

  • 28. H. Yang, How many batches are needed for process validation under the new FDA Guidance?, PDA J. Pharm. Sci. Technol. 67 (2013) 53-62; DOI: 10.5731/pdajpst.2013.00902.CrossrefGoogle Scholar

  • 29. Camo software website, Classical DoE methods and PLS-ANOVA, Specific methods for analyzing designed data; http://www.camo.com/resources/classical-doe-methods-pls-anova.html; access date October 19, 2013.Google Scholar

  • 30. Camo software. User’s manual to Unscrambler X software, v.1.3. Google Scholar

About the article

Accepted: 2014-04-02

Published Online: 2014-10-08

Published in Print: 2014-09-01


Citation Information: Acta Pharmaceutica, ISSN (Online) 1846-9558, DOI: https://doi.org/10.2478/acph-2014-0022.

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© by Anna Krondlová. This work is licensed under the Creative Commons Attribution-NonCommercial-NoDerivatives 3.0 License. BY-NC-ND 3.0

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