Pharmaceutical Research

, Volume 25, Issue 4, pp 781–791 | Cite as

Pharmaceutical Quality by Design: Product and Process Development, Understanding, and Control

  • Lawrence X. YuEmail author
Research Paper



The purpose of this paper is to discuss the pharmaceutical Quality by Design (QbD) and describe how it can be used to ensure pharmaceutical quality.

Materials and Methods

The QbD was described and some of its elements identified. Process parameters and quality attributes were identified for each unit operation during manufacture of solid oral dosage forms. The use of QbD was contrasted with the evaluation of product quality by testing alone.


The QbD is a systemic approach to pharmaceutical development. It means designing and developing formulations and manufacturing processes to ensure predefined product quality. Some of the QbD elements include:
  • Defining target product quality profile

  • Designing product and manufacturing processes

  • Identifying critical quality attributes, process parameters, and sources of variability

  • Controlling manufacturing processes to produce consistent quality over time


Using QbD, pharmaceutical quality is assured by understanding and controlling formulation and manufacturing variables. Product testing confirms the product quality. Implementation of QbD will enable transformation of the chemistry, manufacturing, and controls (CMC) review of abbreviated new drug applications (ANDAs) into a science-based pharmaceutical quality assessment.

Key Words

pharmaceutical quality by design pharmaceutical quality by testing process control process design process parameter process variability product design quality attribute question-based review 



The authors would like to thank Drs. Gregory Amidon, Yihong Qiu, John Strong, Alan Parr, Mansoor Khan, Vincent Vilker, Robert Lionberger, Andre Raw, Lai Ming Lee, Lawrence Sau Lee, Wallace Adams, Doan Nguyen, Michelle Bryden, Gary Buehler, Helen Winkle, and Janet Woodcock for their valuable suggestions.


  1. 1.
    Food and Drug Administration (2003). Final report on pharmaceutical cGMPs for the 21st century—A risk-based approach. (Accessed April 6, 2005).
  2. 2.
    L. X. Yu, A. Raw, R. Lionberger, R. Rajagopalan, L. Lee, F. Holcombe, R. Patel, F. Fang, V. Sayeed, P. Schwartz, R. Adams, and G. Buehler. U.S. FDA question-based review for generic drugs: A new pharmaceutical quality assessment system. J. Generic Med 4:239–248 (2007).CrossRefGoogle Scholar
  3. 3.
    Food and Drug Administration CDER. Guidance for industry, Q8 pharmaceutical development (May 2006).Google Scholar
  4. 4.
    M. Nasr. Risk-based CMC review paradigm. Advisory committee for pharmaceutical science meeting, July 20–21, 2004.Google Scholar
  5. 5.
    Food and Drug Administration CDER. 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 (November 1995).Google Scholar
  6. 6.
    Food and Drug Administration CDER. 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 (September 1997).Google Scholar
  7. 7.
    Food and Drug Administration CDER. Guidance for industry: Nonsterile semisolid dosage forms scale-up and postapproval changes: chemistry, manufacturing, and controls, in vitro dissolution testing, and in vivo bioequivalence documentation (May 1997).Google Scholar
  8. 8.
    Food and Drug Administration CDER. Guidance for industry: Changes to an approved NDA or ANDA (April 2004).Google Scholar
  9. 9.
    J. Woodcock. The concept of pharmaceutical quality. Am. Pharm. Rev. November–December, 1–3, 2004.Google Scholar
  10. 10.
    Food and Drug Administration Office of Generic Drugs White Paper on Question-based Review.
  11. 11.
    Food and Drug Administration CDER. Guidance for industry, Q6A specifications for new drug substances and products: Chemical substances (October 1999).Google Scholar
  12. 12.
    M. Nasr. FDA’s quality initiatives: An update. (Accessed Nov. 10, 2007).
  13. 13.
    IBM Business Consulting Services (2005). Transforming industrialization: A new paradigm for pharmaceutical development.–3997-transforming-industrialization.pdf (Accessed November 16, 2006).
  14. 14.
    Food and Drug Administration.–4228m1.pdf (Accessed November 16, 2006).
  15. 15.
    H. Zhang, and L. X. Yu. Dissolution testing for solid oral drug products: Theoretical considerations. Am. Pharm. Rev., September, 26–31, 2004.Google Scholar
  16. 16.
    J. E. Polli, G. S. Rekhi, L. L. Augsburger, and V. P. Shah. Methods to compare dissolution profiles and a rationale for wide dissolution specifications for metoprolol tartrate tablets. J. Pharm. Sci 86:690–700 (1997).PubMedCrossRefGoogle Scholar
  17. 17.
    R. Takano, K. Sugano, A. Higashida, Y. Hayashi, M. Machida, Y. Aso, and S. Yamashita. Oral aborption of poorly water-soluble drugs: Computer simulation of fraction absorbed in humans from a miniscale dissolution test. Pharm. Res 23:1144–1156 (2006).PubMedCrossRefGoogle Scholar
  18. 18.
    Food and Drug Administration CDER. Guidance for industry, Q3B (R2) impurities in new drug product (July 2006).Google Scholar
  19. 19.
    Food and Drug Administration CDER. Draft guidance for industry, ANDAs: Impurities in drug products (August 2005).Google Scholar
  20. 20.
    J. M. Delasko, D. M. Cocchetto, and L. B. Burke. Target product profile: Beginning drug development with the end in mind. Update, January/February, Issue 1, 2005,
  21. 21.
    Food and Drug Administration CDER. Draft guidance for industry and review staff: Target product profile—A strategic development tool (March 2007).Google Scholar
  22. 22.
    Food and Drug Administration Office of Generic Drugs. Model quality overall summary for IR product. (Accessed March 31, 2006).
  23. 23.
    G. E. Amidon, X. He, M. J. Hageman. Burgers medicinal chemistry and drug discovery, vol 2., Ch 18. In D. J. Abraham (eds). Wiley-Interscience, New York, 2004.Google Scholar
  24. 24.
    L. X. Yu, M. S. Furness, A. Raw, K. P. Woodland Outlaw, N. E. Nashed, E. Ramos, S. P. F. Miller, R. C. Adams, F. Fang, R. M. Patel, F. O. Holcombe Jr., Y. Chiu, and A. S. Hussain. Scientific considerations of pharmaceutical solid polymorphism in abbreviated new drug applications. Pharm. Res 20:531–536 (2003).PubMedCrossRefGoogle Scholar
  25. 25.
    A. S. Raw, M. S. Furness, D. S. Gill, R. C. Adams, F. O. Holcombe Jr., and L. X. Yu. Regulatory considerations of pharmaceutical solid polymorphism in abbreviated new drug applications (ANDAs). Adv. Drug Deliv. Rev 56:397–414 (2004).PubMedCrossRefGoogle Scholar
  26. 26.
    S. P. F. Miller, A. S. Raw, and L. X. Yu. FDA perspective on pharmaceutical solid polymorphism. In R. Hilfiker (ed.), Polymorphism—In the Pharmaceutical and Fine Chemical Industry, Wiley-VCH, New York, 2006.Google Scholar
  27. 27.
    G. E. Amidon. Intrinsic properties of drug substance, excipients, and process selection. FDA OGD regulatory science training series. Manufacturing science and scale-up challenges. May 23, 2005.Google Scholar
  28. 28.
    D. Sun, L. X. Yu, M. A. Hussain, D. A. Wall, R. L. Smith, and G. L. Amidon. In Vitro testing of drug absorption for drug “developability” assessment: Forming an interface between in vitro preclinical data and clinical outcome. Curr Opin Drug Discov Devel. 7:75–85 (2004).Google Scholar
  29. 29.
    L. X. Yu. An integrated absorption model for determining causes of poor oral drug absorption. Pharm. Res 16:1883–1887 (1999).PubMedCrossRefGoogle Scholar
  30. 30.
    L. X. Yu, C. D. Ellison, and A. S. Hussain. Predicting human oral bioavailability using in silico models. In R. Krishna (ed.), Applications of Pharmacokinetics Principles in Drug Development, Kluwer, New York, 2004.Google Scholar
  31. 31.
    G. L. Amidon, H. Lennernas, V. P. Shah, and J. R. Crison. A theoretical basis for a biopharmaceutic drug classification: the correlation of in vitro drug product dissolution and in vivo bioavailability. Pharm. Res 12:413–420 (1995).PubMedCrossRefGoogle Scholar
  32. 32.
    Food and Drug Administration CDER. Guidance for industry, Waiver of In Vivo Bioavailability and Bioequivalence Studies for Immediate Release Solid Oral Dosage Forms Based on a Biopharmaceutics Classification System. August 2000, CDER/FDA.Google Scholar
  33. 33.
    L. X. Yu, G. L. Amidon, J. E. Polli, H. Zhao, M. Mehta, D. P. Conner, V. P. Shah, L. J. Lesko, M.-L. Chen, V. H. L. Lee, and A. S. Hussain. Biopharmaceutics Classification System: The scientific basis for biowaiver extension. Pharm. Res 19:921–925 (2002).PubMedCrossRefGoogle Scholar
  34. 34.
    J. E. Polli, L. X. Yu, J. A. Cook, G. L. Amidon, R. T. Borchardt, B. A. Burnside, P. S. Burton, M. L. Chen, D. P. Conner, P. J. Faustino, A. A. Hawi, A. S. Hussain, H. N. Joshi, G. Kwei, V. H. L. Lee, L. J. Lesko, R. A. Lipper, A. E. Loper, S. G. Nerurkar, J. W. Polli, D. R. Srdeker, R. Taneja, R. S. Uppoor, C. S. Vattikonda, I. Wilding, and G. Zhang. Summary workshop report: Biopharmaceutics classification system – implementation challenges and extension opportunities. J. Pharm. Sci 93:1375–81 (2004).PubMedCrossRefGoogle Scholar
  35. 35.
    G. E. Amidon. Physical and mechanical property characterization of powders. In H. G. Brittain (ed.), Physical Characterization of Pharmaceutical Solid. Marcel Dekker, New York 1995, pp. 281–320.Google Scholar
  36. 36.
    S. Jain. Mechanical properties of powders for compaction and tableting: an overview. PSTT 2:20–31 (1999).Google Scholar
  37. 37.
    H. Dubin. Formulation frustrations. Drug Deliv. Technol. 5(8), 2005 (September).Google Scholar
  38. 38.
    R. K. Verma, and S. Garg. Selection of excipients for extended release formulations of glipizide through drug-excipient compatibility testing. Int. J. Pharm. Biomed. Ana 38:633–644 (2005).CrossRefGoogle Scholar
  39. 39.
    K. C. Waterman, and R. C. Adami. Accelerated aging: Prediction of chemical stability of pharmaceuticals. Int. J. Pharm 293:101–125 (2005).PubMedCrossRefGoogle Scholar
  40. 40.
    R. Kandarapu, V. Grover, H. P. S. Chawla, and S. Garg. S. T. P. Pharma Sci 11:449–457 (2001).Google Scholar
  41. 41.
    A. T. M. Serajuddin, A. B. Thakur, R. N. Ghoshal, M. G. Fakes, S. A. Ranadive, K. R. Morris, and S. A. Varia. Selection of solid dosage form composition through drug-excipient compatibility testing. J. Pharm. Sci 88:696–704 (1999).PubMedCrossRefGoogle Scholar
  42. 42.
    M. Gibson. Product optimization. In M. Gibson (ed.), Pharmaceutical Preformulation and Formulation. Taylor & Francis, New York, 2001, pp. 295–330.Google Scholar
  43. 43.
    M. D. Tousey. The granulation process 101, basic technologies for tablet making. Pharm. Tech. Tableting and Granulation. 2002.Google Scholar
  44. 44.
    D. P. Petrides, A. Koulouris, and P. T. Lagonikos. The Role of process simulation in pharmaceutical process development and product commercialization. Pharm. Eng 22:1–8 (2002).Google Scholar
  45. 45.
    W. P. Ganzer, J. A. Materna, M. B. Mitchell, and L. K. Wall. Current thoughts on critical process parameters (CPP’s) and API Syntheses. Pharm Tech., July 2, 2005.Google Scholar
  46. 46.
    F. A. Menard. Quality by design in generic drug development. Presentation to FDA Office of Generic Drugs. September 25, 2006.Google Scholar
  47. 47.
    M. Glodek, S. Liebowitz, R. mcCarthy, G. McNally, C. Oksanen, T. Schultz, M. Sundararajan, R. Vorkapich, K. Vukovinsky, C. Watts, and G. Millili. Process robustness—A PQRI white paper. Pharm. Eng 26:1–11 (2006).Google Scholar
  48. 48.
    Rath and Strong. Design for six-sigma pocket guide. Rath and Strong Management Consutants/AON Management Consulting, Lexington, MA (2002).Google Scholar
  49. 49.
    C. Chen. Implementing quality by design: ONDQA initiatives. Advisory Committee for Pharmaceutical Science October 5, 2006.–4241s1-index.htm (Accessed December 1, 2006).
  50. 50.
    National Institute for Pharmaceutical Technology and Education. Strategic roadmap for research and education. (2006).
  51. 51.
    Food and Drug Administration CDER. Guidance for industry, PAT—A framework for innovative pharmaceutical development, manufacturing, and quality assurance. September 2006.Google Scholar
  52. 52.
    L. X. Yu, R. A. Lionberger, A. S. Raw, R. D’Costa, H. Wu, and A. S. Hussain. Application of process analytical technology to crystallization process. Adv. Drug Del. Rev 56:349–369 (2004).CrossRefGoogle Scholar
  53. 53.
    C. Watts, and J. E. Clark. PAT: Driving the future of pharmaceutical quality. J. Pro. Ana. Tech 3(6):6–9 (2006).Google Scholar

Copyright information

© US Government: Food and Drug Administration 2007

Authors and Affiliations

  1. 1.Food and Drug AdministrationOffice of Generic DrugsRockvilleUSA

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