The AAPS Journal

, Volume 11, Issue 3, pp 414–423 | Cite as

In Vitro Considerations to Support Bioequivalence of Locally Acting Drugs in Dry Powder Inhalers for Lung Diseases

  • Sau Lawrence LeeEmail author
  • Wallace P. Adams
  • Bing V. Li
  • Dale P. Conner
  • Badrul A. Chowdhury
  • Lawrence X. Yu
Regulatory Note


Dry powder inhalers (DPIs) are used to deliver locally acting drugs (e.g., bronchodilators and corticosteroids) for treatment of lung diseases such as asthma and chronic obstructive pulmonary disease (COPD). Demonstrating bioequivalence (BE) for DPI products is challenging, primarily due to an incomplete understanding of the relevance of drug concentrations in blood or plasma to equivalence in drug delivery to the local site(s) of action. Thus, BE of these drug/device combination products is established based on an aggregate weight of evidence, which utilizes in vitro studies to demonstrate equivalence of in vitro performance, pharmacokinetic or pharmacodynamic studies to demonstrate equivalence of systemic exposure, and pharmacodynamic and clinical endpoint studies to demonstrate equivalence in local action. This review discusses key aspects of in vitro studies in supporting the establishment of BE for generic locally acting DPI products. These aspects include comparability in device resistance and equivalence in in vitro testing for single inhalation (actuation) content and aerodynamic particle size distribution.

Key words

bioequivalence (BE) dry powder inhaler (DPI) locally acting drugs particle size distribution single inhalation (actuation) content 


  1. 1.
    Weibel ER. Morphometry of the human lung. Berlin: Springer; 1963.Google Scholar
  2. 2.
    Hickey AJ, Thompson DC. Physiology of the airways. In: Hickey AJ, editor. Pharmaceutical inhalation aerosol technology. 2nd ed. New York: Marcel Dekker; 2004. p. 1–29.Google Scholar
  3. 3.
    Carstairs JR, Nimmo AJ, Barnes PJ. Autoradiographic visualization of beta-adrenoceptor subtypes in human lung. Am Rev Respir Dis. 1985;132:541–7.PubMedGoogle Scholar
  4. 4.
    Usmani OS, Biddiscombe MF, Barnes PJ. Regional lung deposition and bronchodilator response as a function of β2-agonist particle size. Am J Respir Crit Care Med. 2005;172:1497–504.PubMedCrossRefGoogle Scholar
  5. 5.
    Mak JC, Barnes PJ. Autoradiographic visualization of muscarinic receptor subtypes in human and guinea pig lung. Am Rev Respir Dis. 1990;141:1559–68.PubMedGoogle Scholar
  6. 6.
    Kraft M, Djukanovic R, Wilson S, Holgate ST, Martin RJ. Alveolar tissue inflammation in asthma. Am J Respir Crit Care Med. 1996;154:1505–10.PubMedGoogle Scholar
  7. 7.
    Carroll N, Cooke C, James A. The distribution of eosinophils and lymphocytes in the large and small airways of asthmatics. Eur Respir J. 1997;10:292–300.PubMedCrossRefGoogle Scholar
  8. 8.
    Sbirlea-Apiou G, Katz I, Caillibotte G, Martonen T, Yang Y. Deposition mechanics of pharmaceutical particles in human airways. In: Hickey AJ, editor. Inhalation aerosols: physical and biological basis for therapy. 2nd ed. New York: Informia Healthcare; 2007. p. 1–30.Google Scholar
  9. 9.
    Zanen P, Go LT, Lammers JW. Optimal particle size for beta 2 agonist and anticholinergic aerosols in patients with severe airflow obstruction. Thorax. 1996;51:977–80.PubMedCrossRefGoogle Scholar
  10. 10.
    Sangwan S, Agosti JM, Bauer LA, Otulana BA, Morishige RJ, Cipolla DC, et al. Aerosolized protein delivery in asthma: gamma camera analysis of regional deposition and perfusion. J Aerosol Med. 2001;14:185–95.PubMedCrossRefGoogle Scholar
  11. 11.
    Newman SP, Hirst PH, Pitcairn GR, Clark AR. Understanding regional lung deposition data in gamma scintigraphy. In: Dalby RN, Byron PR, Farr SJ, editors. Respiratory drug delivery VI. Buffalo Grove: Interpharm; 1998. p. 9–16.Google Scholar
  12. 12.
    Esposito-Festen JE, Zanen P, Tiddens HA, Lammers JW. Pharmacokinetics of inhaled monodisperse beclomethasone as a function of particle size. Br J Clin Pharmacol. 2007;64:328–34.PubMedCrossRefGoogle Scholar
  13. 13.
    Whale CI. Safety aspects of β2-agonists in chronic obstructive pulmonary disease. A thesis submitted to the University of Nottingham for the degree of Doctor of Medicine, November 2007. Accessed 30 Mar 2009.
  14. 14.
    Zanen P, Go LT, Lammers J-W. The optimal particle size for β-adrenergic aerosols in mild asthmatics. Int J Pharm. 1994;107:211–7.CrossRefGoogle Scholar
  15. 15.
    Zanen P, Go LT, Lammers J-WJ. The optimal particle size for parasympathicolytic aerosols in mild asthmatics. Int J Pharm. 1995;114:111–5.CrossRefGoogle Scholar
  16. 16.
    Usmani OS, Biddiscombe MF, Nightingale JA, Underwood SR, Barnes PJ. Effects of bronchodilator particle size in asthmatic patients using monodisperse aerosols. J Appl Physiol. 2003;95:2106–12.PubMedGoogle Scholar
  17. 17.
    Weda M. The clinical impact of changing the fine particle mass data obtained with albuterol DPIs. In: Dalby RN, Byron PR, Peart J, Suman JD, Farr SJ, Young PM, editors. Respiratory drug delivery 2008: Book I. River Grove, IL: Davis Healthcare International; 2008. p. 85–92.Google Scholar
  18. 18.
    Fults KA, Miller IF, Hickey AJ. Effect of particle morphology on emitted dose of fatty acid-treated disodium cromoglycate powder aerosols. Pharm Dev Technol. 1997;2:67–79.PubMedCrossRefGoogle Scholar
  19. 19.
    Dunbar CA, Hickey AJ, Holzner P. Dispersion and characterization of pharmaceutical dry powder aerosols. Kona. 1998;16:7–45.Google Scholar
  20. 20.
    Gonda I. Targeting by deposition. In: Hickey AJ, editor. Pharmaceutical inhalation aerosol technology. 2nd ed. New York: Marcel Dekker; 2004. p. 65–88.Google Scholar
  21. 21.
    Telko MJ, Hickey AJ. Dry powder inhaler formulation. Respir Care. 2005;50:1209–27.PubMedGoogle Scholar
  22. 22.
    Ganderton D, Kassem NM. Dry powder inhalers. Adv Pharm Sci. 1992;6:165–91.Google Scholar
  23. 23.
    Schreier H, Mobley WC, Concessio N, Hickey AJ, Niven RW. Formulation and in vitro performance of liposome powder aerosols. STP Pharma Sci. 1994;4:38–44.Google Scholar
  24. 24.
    Staniforth JN, Rees JE, Lai FK, Hersey JA. Interparticle forces in binary and ternary ordered powder mixes. J Pharm Pharmacol. 1982;34:141–5.PubMedGoogle Scholar
  25. 25.
    Islam N, Stewart P, Larson I, Hartley P. Effect of carrier size on the dispersion of salmeterol xinafoate from interactive mixtures. J Pharm Sci. 2004;93:1030–8.PubMedCrossRefGoogle Scholar
  26. 26.
    Louey MD, Stewart PJ. Particle interactions involved in aerosol dispersion of ternary interactive mixtures. Pharm Res. 2002;19:1524–31.PubMedCrossRefGoogle Scholar
  27. 27.
    de Boer AH, Gjaltema D, Hagedoorn P. Inhalation characteristics and their effects on in vitro drug delivery from dry powder inhalers Part 2: effect of peak flow rate (PIFR) and inspiration time on the in vitro drug release from three different types of commercial dry powder inhalers. Int J Pharm. 1996;138:45–56.CrossRefGoogle Scholar
  28. 28.
    Carter PA, Rowley G, Fletcher EJ, Stylianopoulos V. Measurement of electrostatic charge decay in pharmaceutical powders and polymer materials used in dry powder inhaler devices. Drug Dev Ind Pharm. 1998;24:1083–8.PubMedCrossRefGoogle Scholar
  29. 29.
    Dalby RN, Tiano SL, Hickey AJ. Medical devices for the delivery of therapeutic aerosols to the lungs. In: Hickey AJ, editor. Inhalation aerosols: physical and biological basis for therapy. 2nd ed. New York: Informa Healthcare; 2007. p. 417–44.Google Scholar
  30. 30.
    Chrystyn H. The DiskusTM: a review of its position among dry powder inhaler devices. Int J Clin Pract. 2007;61:1022–36.PubMedCrossRefGoogle Scholar
  31. 31.
    Molimard M, Raherison C, Lignot S, Depont F, Abouelfath A, Moore N. Assessment of handling of inhaler devices in real life: an observational study in 3811 patients in primary care. J Aerosol Med. 2003;16:249–54.PubMedCrossRefGoogle Scholar
  32. 32.
    Hindle M, Byron PR. Dose emissions from marketed dry powder inhalers. Int J Pharm. 1995;116:169–77.CrossRefGoogle Scholar
  33. 33.
    Mitchell JP, Nagel MW. Cascade impactors for the size characterization of aerosols from medical inhalers: their uses and limitations. J Aerosol Med. 2003;16:341–77.PubMedCrossRefGoogle Scholar
  34. 34.
    Meakin BJ, Cainey JM, Woodcock PM. Drug delivery characteristics of Bricanyl Turbohaler™ dry powder inhalers. Int J Pharm. 1995;119:91–102.CrossRefGoogle Scholar
  35. 35.
    Newman SP, Chan H-K. In vitro/in vivo comparisons in pulmonary drug delivery. J Aerosol Med Pul Drug Delivery. 2008;21:77–84.CrossRefGoogle Scholar

Copyright information

© American Association of Pharmaceutical Scientists 2009

Authors and Affiliations

  • Sau Lawrence Lee
    • 1
    Email author
  • Wallace P. Adams
    • 1
  • Bing V. Li
    • 1
  • Dale P. Conner
    • 1
  • Badrul A. Chowdhury
    • 2
  • Lawrence X. Yu
    • 1
  1. 1.Office of Generic Drugs, Center for Drug Evaluation and ResearchU.S. Food and Drug AdministrationRockvilleUSA
  2. 2.Division of Pulmonary and Allergy Products, Office of New Drugs, Center for Drug Evaluation and ResearchU.S. Food and Drug AdministrationSilver SpringUSA

Personalised recommendations