The AAPS Journal

, Volume 16, Issue 4, pp 771–783 | Cite as

Understanding Pharmaceutical Quality by Design

  • Lawrence X. Yu
  • Gregory Amidon
  • Mansoor A. Khan
  • Stephen W. Hoag
  • James Polli
  • G. K. Raju
  • Janet Woodcock
Review Article

Abstract

This review further clarifies the concept of pharmaceutical quality by design (QbD) and describes its objectives. QbD elements include the following: (1) a quality target product profile (QTPP) that identifies the critical quality attributes (CQAs) of the drug product; (2) product design and understanding including identification of critical material attributes (CMAs); (3) process design and understanding including identification of critical process parameters (CPPs), linking CMAs and CPPs to CQAs; (4) a control strategy that includes specifications for the drug substance(s), excipient(s), and drug product as well as controls for each step of the manufacturing process; and (5) process capability and continual improvement. QbD tools and studies include prior knowledge, risk assessment, mechanistic models, design of experiments (DoE) and data analysis, and process analytical technology (PAT). As the pharmaceutical industry moves toward the implementation of pharmaceutical QbD, a common terminology, understanding of concepts and expectations are necessary. This understanding will facilitate better communication between those involved in risk-based drug development and drug application review.

KEY WORDS

control strategy critical quality attributes pharmaceutical quality by design process understanding product understanding 

Notes

Acknowledgment

The authors would like to thank Lane V. Christensen, Devinder Gill, Frank Holcombe Jr, Robert Iser, Khalid Khan, Robert Lionberger, Jennifer Maguire, Christine Moore, Yingxu (Daniel) Peng, Andre Raw, Bhagwant Rege, Susan Rosencrance, Vilayat Sayeed, Paul Schwartz, Glen Smith, Yue (Helen) Teng, Youmin Wang, Huiquan Wu, Abhay Gupta, Ziyaur Rahman, and Naiqi Ya for their valuable suggestions.

References

  1. 1.
    Juran JM. Juran on quality by design: the new steps for planning quality into goods and services. New York: The Free Press; 1992.Google Scholar
  2. 2.
    Woodcock J. The concept of pharmaceutical quality. Am Pharm Rev 2004; 1–3.Google Scholar
  3. 3.
    U. S. Food and Drug Administration. Guidance for Industry: Q8 (2) Pharmaceutical Development. 2009Google Scholar
  4. 4.
    U. S. Food and Drug Administration. Guidance for Industry: Q9 Quality Risk Management. 2006.Google Scholar
  5. 5.
    U. S. Food and Drug Administration. Guidance for Industry: Q10 pharmaceutical quality system. 2009.Google Scholar
  6. 6.
    U. S. Food and Drug Administration. Guidance for Industry: Q8, Q9, and Q10 questions and answers. 2011.Google Scholar
  7. 7.
    ICH Quality Implementation Working Group. Points to consider. ICH-endorsed guide for ICH Q8/Q9/Q10 implementation. 2011.Google Scholar
  8. 8.
    U. S. Food and Drug Administration. Guidance for Industry: Q11 development and manufacture of drug substance. 2012.Google Scholar
  9. 9.
    U. S. Food and Drug Administration. FDA-EMA parallel assessment of Quality-By-Design elements of marketing applications. http://www.fda.gov/Drugs/DrugSafety/ucm365524.htm. Accessed 16 Nov 2013
  10. 10.
    Yu LX. Pharmaceutical quality by design: product and process development, understanding, and control. Pharm Res. 2008;25:781–91.PubMedCrossRefGoogle Scholar
  11. 11.
    Lionberger R, Lee S, Lee L, Raw A, Yu LX. Quality by design: concepts for ANDAs. AAPS J. 2008;10:268–76.PubMedCentralPubMedCrossRefGoogle Scholar
  12. 12.
    Raw AS, Lionberger R, Yu LX. Pharmaceutical equivalence by design for generic drugs: modified-release products. Pharm Res. 2011;28:1445–53.PubMedCrossRefGoogle Scholar
  13. 13.
    Rathore AS, Winkle H. Quality by design for biopharmaceuticals. Nat Biotechnol. 2009;27:26–34.PubMedCrossRefGoogle Scholar
  14. 14.
    U. S. Food and Drug Administration. Guidance for Industry: tablet scoring: nomenclature, labeling, and data for evaluation. 2013.Google Scholar
  15. 15.
    U. S. Food and Drug Administration. Guidance for Industry: Size of Beads in Drug Products Labeled for Sprinkle. January, 2011.Google Scholar
  16. 16.
    U. S. Food and Drug Administration. Summary Minutes of the Advisory Committee for Pharmaceutical Science and Clinical Pharmacology. July 26, 2011. http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/AdvisoryCommitteeforPharmaceuticalScienceandClinicalPharmacology/UCM272111.pdf. Accessed 13 Aug 2013.
  17. 17.
    U. S. Food and Drug Administration. Guidance for industry: immediate release solid oral dosage forms scale-up and postapproval changes: chemistry, manufacturing, and controls, in vitro dissolution testing, and in vivo bioequivalence documentation. 1995.Google Scholar
  18. 18.
    U. S. Food and Drug Administration. Guidance for industry: modified release solid oral dosage forms scale-up and postapproval changes: chemistry, manufacturing, and controls, in vitro dissolution testing, and in vivo bioequivalence documentation. 1997.Google Scholar
  19. 19.
    U. S. Food and Drug Administration. Guidance for industry: CMC postapproval manufacturing changes to be documented in annual reports. 2014.Google Scholar
  20. 20.
    U. S. Food and Drug Administration. Quality by design for ANDs: an example for immediate-release dosage forms. 2012. http://www.fda.gov/downloads/Drugs/DevelopmentApprovalProcess/HowDrugsareDevelopedandApproved/ApprovalApplications/AbbreviatedNewDrugApplicationANDAGenerics/UCM304305.pdf. Accessed 16 Nov 2013.
  21. 21.
    U. S. Food and Drug Administration. Quality by design for ANDs: an example for modified-release dosage forms. 2011. http://www.fda.gov/downloads/Drugs/DevelopmentApprovalProcess/HowDrugsareDevelopedandApproved/ApprovalApplications/AbbreviatedNewDrugApplicationANDAGenerics/UCM304305.pdf. Accessed 16 Nov 2013.
  22. 22.
  23. 23.
    USP 34—NF 29 (United States Pharmacopeial Convention). Chapter 1078. Good manufacturing practice for bulk pharmaceutical excipients. Rockville, MD: USP; 2011, pp. 1415–1420Google Scholar
  24. 24.
    USP 34—NF 29 (United States Pharmacopeial Convention). USP and NF Excipients, Listed by Category. Rockville, MD: USP; 2011, pp. 583–595.Google Scholar
  25. 25.
    U. S. Food and Drug Administration. Inactive Ingredient Search for Approved Drug Products. http://www.accessdata.fda.gov/scripts/cder/iig/index.cfm, Accessed 13 Aug 2013.
  26. 26.
    Nazzal S, Nutan M, Palamakula A, Shah R, Zaghloul AA, Khan MA. Optimization of a self-nanoemulsified tablet dosage form of ubiquinone using response surface methodology: effect of formulation ingredients. Int J Pharm. 2002;240:103–14.PubMedCrossRefGoogle Scholar
  27. 27.
    Awotwe-Otoo D, Agarabi C, Wu GK, Casey E, Read E, Lute S, et al. Quality by design: impact of formulation variables and their interactions on quality attributes of a lyophilized monoclonal antibody. Int J Pharm. 2012;438(1–2):167–75.PubMedCrossRefGoogle Scholar
  28. 28.
    U.S. Food and Drug Administration CDER. Guidance for industry: PAT—a framework for innovative pharmaceutical development, manufacturing, and quality assurance. 2004.Google Scholar
  29. 29.
    Glodek M, Liebowitz S, McCarthy R, McNally G, Oksanen C, Schultz T, et al. Process robustness—a PQRI white paper. Pharm Eng. 2006;26:1–11.Google Scholar
  30. 30.
    NIST/SEMATECH e-Handbook of Statistical Methods. What is process capability? http://www.itl.nist.gov/div898/handbook/pmc/section1/pmc16.htm. Accessed on 13 Aug 2013.
  31. 31.
    ASTM E2281—08a (2012)e1 Standard practice for process and measurement capability indices. http://www.astm.org/Standards/E2281.htm. Accessed 13 Aug 2013.
  32. 32.
    De Feo JA, Barnard W. JURAN Institute's six sigma breakthrough and beyond—quality performance breakthrough methods. India: Tata McGraw-Hill Publishing Company Limited; 2005.Google Scholar
  33. 33.
    Wu H, Khan MA. Quality-by-design (QbD): an integrated approach for evaluation of powder blending process kinetics and determination of powder blending end-point. J Pharm Sci. 2009;98(8):2784–98.PubMedCrossRefGoogle Scholar
  34. 34.
    Rahman Z, Siddiqui A, Khan MA. Assessing the impact of nimodipine devitrification in the ternary cosolvent system through quality by design approach. Int J Pharm. 2013;455(1–2):113–23.PubMedCrossRefGoogle Scholar
  35. 35.
    Rahman Z, Siddiqui A, Khan MA. Orally disintegrating tablet of novel salt of antiepileptic drug: formulation strategy and evaluation. Eur J Pharm Biopharm. 2013;85:1300–9.PubMedCrossRefGoogle Scholar
  36. 36.
    Zidan AS, Sammour OA, Hammad MA, Megrab NA, Habib MJ, Khan MA. Quality by design: understanding the formulation variables of a cyclosporine, a self-nanoemulsified drug delivery systems by Box-Behnken design and desirability function. Int J Pharm. 2007;332(1–2):55–63.PubMedCrossRefGoogle Scholar
  37. 37.
    Xu X, Khan MA, Burgess DJ. A Quality by design (QbD) case study on liposomes containing hydrophilic API: II. Screening of critical variables, and establishment of design space at laboratory scale. Int J Pharm. 2012;423(2):543–53.PubMedCrossRefGoogle Scholar
  38. 38.
    Yerlikaya F, Ozgen A, Vural I, Guven O, Karaagaoglu E, Khan MA, et al. Development and evaluation of paclitaxel nanoparticles using a quality-by-design (QbD) approach. J Pharm Sci. 2013;102(10):3748–61.PubMedCrossRefGoogle Scholar
  39. 39.
    Rahman Z, Khan MA. Hunter screening design to understand the product variability of solid dispersion formulation of a peptide antibiotic. Int J Pharm. 2013;456(2):572–82.PubMedCrossRefGoogle Scholar
  40. 40.
    Yu LX, Lionberger RA, Raw AS, D'Costa R, Wu H, Hussain AS. Application of process analytical technology to crystallization process. Adv Drug Deliv Rev. 2004;56(3):349–69.PubMedCrossRefGoogle Scholar
  41. 41.
    Wu H, Khan MA. Quality-by-design (QbD): an integrated multivariate approach for the component quantification in powder blends. Int J Pharm. 2009;372(1–2):39–48.PubMedCrossRefGoogle Scholar
  42. 42.
    Wu H, Khan MA. Quality-by-design (QbD): an integrated process analytical technology (pat) approach to determine the nucleation and growth mechanisms during a dynamic pharmaceutical co-precipitation process. J Pharm Sci. 2011;100(5):1969–86.PubMedCrossRefGoogle Scholar
  43. 43.
    Rahman Z, Siddiqui A, Khan MA. Characterization of a nonribosomal peptide antibiotic solid dispersion formulation by process analytical technologies sensors. J Pharm Sci. 2013;102(12):4337–46.PubMedCrossRefGoogle Scholar
  44. 44.
    Xu X, Siddiqui A, Khan MA. Focused beam reflectance measurement to monitor nimodipine precipitation process. Int J Pharm. 2013;456(2):353–6.PubMedCrossRefGoogle Scholar

Copyright information

© American Association of Pharmaceutical Scientists 2014

Authors and Affiliations

  • Lawrence X. Yu
    • 1
  • Gregory Amidon
    • 2
  • Mansoor A. Khan
    • 1
  • Stephen W. Hoag
    • 3
  • James Polli
    • 3
  • G. K. Raju
    • 4
    • 5
  • Janet Woodcock
    • 1
  1. 1.Center for Drug Evaluation and ResearchFood and Drug AdministrationSilver SpringUSA
  2. 2.University of MichiganAnn ArborUSA
  3. 3.University of MarylandBaltimoreUSA
  4. 4.Massachusetts Institute of TechnologyCambridgeUSA
  5. 5.Light Pharm Inc.CambridgeUSA

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