Skip to main content
NCBI home page
AAPS PharmSciTech logoLink to AAPS PharmSciTech
. 2007 Jan 19;8(1):E39–E48. doi: 10.1208/pt0801005

Product Quality Research Institute evaluation of cascade impactor profiles of pharmaceutical aerosols: Part 2—Evaluation of a method for determining equivalence

David Christopher 1,✉, Wallace P Adams 2, Douglas S Lee 3, Beth Morgan 4, Ziqing Pan 5, Gur Jai Pal Singh 2, Yi Tsong 7, Svetlana Lyapustina 8,✉
PMCID: PMC2750440  PMID: 17408228

Abstract

The purpose of this article is to present the thought process, methods, and interim results of a PQRI Working Group, which was charged with evaluating the chi-square ratio test as a potential method for determining in vitro equivalence of aerodynamic particle size distribution (APSD) profiles obtained from cascade impactor measurements. Because this test was designed with the intention of being used as a tool in regulatory review of drug applications, the capability of the test to detect differences in APSD profiles correctly and consistently was evaluated in a systematic way across a designed space of possible profiles. To establish a “base line,” properties of the test in the simplest case of pairs of identical profiles were studied. Next, the test's performance was studied with pairs of profiles, where some difference was simulated in a systematic way on a single deposition site using realistic product profiles. The results obtained in these studies, which are presented in detail here, suggest that the chi-square ratio test in itself is not sufficient to determine equivalence of particle size distributions. This article, therefore, introduces the proposal to combine the chi-square ratio test with a test for impactor-sized mass based on Population Bioequivalence and describes methods for evaluating discrimination capabilities of the combined test. The approaches and results described in this article elucidate some of the capabilities and limitations of the original chi-square ratio test and provide rationale for development of additional tests capable of comparing APSD profiles of pharmaceutical aerosols.

Keywords: Chi-square ratio, bioequivalence, cascade impactor, particle size distribution

Full Text

The Full Text of this article is available as a PDF (536.2 KB).

References

  • 1.FDA/CDER. Draft Guidance for Industry: Bioavailability and Bioequivalence Studies for Nasal Aerosols and Nasal Sprays for Local Action.Food and Drug Administration Web site. 1999. Available at: http://www.fda.gov/eder/guidance/2070DFT.pdf. Accessed: April 17, 2006.
  • 2.Adams WP, Christopher D, Lee DS, et al. PQRI evaluation of cascade impactor profiles of pharmaceutical aerosols: Part 1—Background for a statistical method.AAPS Pharm Sci Tech. In press. [DOI] [PMC free article] [PubMed]
  • 3.PQRI PSD Profile Comparisons Working Group. Work plan for the investigation of an optimized chi-square method for comparing particle size distribution profiles obtained by cascade impactors with specific reference to equivalence testing of orally inhaled and pressurized nasal drug products. 2002. Available at: http://www.pqri.org/commworking/ minutes/pdfs/dpte/psdpcwg/workplan02.pdf. Accessed: August 18, 2006.
  • 4.Tsong Y. Statistical comparison of particle size distribution profiles. 2004. Available at: http://pqri.org/commworking/minutes/pdfs/dptc/ psdpcwg/Addl/DC01-475116-v2-Yi_Tsong_Statistical_Archive_PQRI_Profile_Comparisons. DOC. Accessed: April 20, 2006.
  • 5.Lee D. Searching for the holy grail of a single PSD profile comparator. 2004. Available at: http://pqri.org/commworking/minutes/ pdfs/dptc/psdpcwg/Addl/DC01-504108-v1-Identical_Profiles_and_Stability_Slides. PPT. Accessed: April 20, 2006.
  • 6.Lee D. Searching for the holy grail of a single PSD profile comparator: technical challenges with the chi-squared ratio approach. In: Dalby RN, Byron PR, Peart J, Suman JD, Farr SJ, editors. Respiratory Drug Delivery IX: Biological, Pharmaceutical, Clinical, and Regulatory Issues Relating to Optimized Drug Delivery by Aerosol. River Grove, IL: Davis Healthcare International Publishing; 2004. pp. 161–169. [Google Scholar]
  • 7.Pan Z, Christopher JD, Lyapustina S, Chou E. Statistical techniques used in simulation of cascade impactor particle size distribution profiles. In: Dalby RN, Byron PR, Peart J, Suman JD, Farr SJ, editors. Respiratory Drug Delivery IX: Biological, Pharmaceutical, Clinical, and Regulatory Issues Relating to Optimized Drug Delivery by Aerosol. River Grove, IL: Davis Healthcare International Publishing; 2004. pp. 669–672. [Google Scholar]
  • 8.PQRI Profile Comparisons Working Group. Systematic Study of 38 Scenarios. 2005. Available at: http://pqri.org/commworking/minutes/ pdfs/dpte/psdpcwg/Addl/38%20Systematic%20Scenarios.pdf.Accessed: August 17, 2006.
  • 9.PQRI PSD Profile Comparison Working Group. Draft simulation results on stability of the chi-square ratio statistic under the null case of identical sets of reference and test profiles. 2002. Available at: http:// pqri.org/commworking/minutes/pdfs/dptc/psdpcwg/Addl/DC01-504131-vl-PQRI_Profile_Comparisons_Slides_for_DPTC.PPT.Accessed: August 17, 2006.
  • 10.PQRI PSD Profile Comparisons Working Group. Minutes of the teleconference on 7 July 2004:7–8. Available at: http://pqri.org/ commworking/minutes/pdfs/dpte/psdpewg/070704min.pdf. Accessed: August 17, 2006.
  • 11.PQRI PSD Profile Comparisons Working Group. Minutes of the teleconference on 27 October 2004:3–7. Available at: http://pqri.org/ commworking/minutes/pdfs/dptc/psdpcwg/102704min.pdf. Accessed: August 17, 2006.
  • 12.PQRI PSD Profile Comparisons Working Group. Minutes of the teleconference on 22 September 2004:4–14. Available at: http://pqri.org/ commworking/minutes/pdfs/dpte/psdpewg/092204min.pdf. Accessed: August 17, 2006.
  • 13.Christopher D, Ziqing P, Lyapustina A. Aerodynamic particle size distribution profile comparison: considerations for assessing statistical properties of profile comparison tests. Am Pharm Rev. 2005;8:68–72. [Google Scholar]
  • 14.PQRI PSD Profile Comparisons Working Group. Minutes of the teleconference December 14, 2005:7. Available at: http://pqri.org/ commworking/minutes/pdfs/dpte/psdpcwg/121405min.pdf. Accessed: August 18, 2006.
  • 15.PQRI PSD Profile Comparisons Working Group. Minutes of the teleconference February 16, 2005:5–6. Available at: http://pqri.org/ commworking/minutes/pdfs/dpte/psdpcwg/021605min.pdf. Accessed: August 17, 2006.
  • 16.Hauck W. Statistical analysis, equivalence and inequivalence: an overview of data reporting. Presentation at AAPS/FDA/USP Workshop: Particle Size Analysis; April 30 to May 2, 2003; Washington, DC.
  • 17.Christopher D, Curry P, Doub B, et al. Considerations for the development and practice of cascade impaction testing, including a mass balance failure investigation tree. J Aerosol Med. 2003;16:235–247. doi: 10.1089/089426803769017604. [DOI] [PubMed] [Google Scholar]
  • 18.Mitchell JP. Regarding the development and practice of cascade impaction testing, including a mass balance failure investigation tree. J Aerosol Med. 2003;16:433–433. doi: 10.1089/089426803772455686. [DOI] [PubMed] [Google Scholar]
  • 19.Newman SP, Wilding IR, Hirst PH. Human lung deposition data: the bridge between in vitro and clinical evaluations for inhaled drug products. Int J Pharm. 2000;208:49–60. doi: 10.1016/S0378-5173(00)00538-X. [DOI] [PubMed] [Google Scholar]
  • 20.Hinds WC. Aerosol Technology: Properties, Behavior; and Measurement of Airborne Particles. New York, NY: John Wiley & Sons; 1999. pp. 75–110. [Google Scholar]
  • 21.Dunbar C, Mitchell J. Analysis of cascade impactor mass distributions. J Aerosol Med. 2005;18:439–451. doi: 10.1089/jam.2005.18.439. [DOI] [PubMed] [Google Scholar]

Articles from AAPS PharmSciTech are provided here courtesy of American Association of Pharmaceutical Scientists

RESOURCES