Discriminating Ability of Abbreviated Impactor Measurement Approach (AIM) to Detect Changes in Mass Median Aerodynamic Diameter (MMAD) of an Albuterol/Salbutamol pMDI Aerosol
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This article reports on results from a two-lab, multiple impactor experiment evaluating the abbreviated impactor measurement (AIM) concept, conducted by the Cascade Impaction Working Group of the International Pharmaceutical Aerosol Consortium on Regulation and Science (IPAC-RS). The goal of this experiment was to expand understanding of the performance of an AIM-type apparatus based on the Andersen eight-stage non-viable cascade impactor (ACI) for the assessment of inhalation aerosols and sprays, compared with the full-resolution version of that impactor described in the pharmacopeial compendia. The experiment was conducted at two centers with a representative commercially available pressurized metered dose inhaler (pMDI) containing albuterol (salbutamol) as active pharmaceutical ingredient (API). Metrics of interest were total mass (TM) emitted from the inhaler, impactor-sized mass (ISM), as well as the ratio of large particle mass (LPM) to small particle mass (SPM). ISM and the LPM/SPM ratio together comprise the efficient data analysis (EDA) metrics. The results of the comparison demonstrated that in this study, the AIM approach had adequate discrimination to detect changes in the mass median aerodynamic diameter (MMAD) of the ACI-sampled aerodynamic particle size distribution (APSD), and therefore could be employed for routine product quality control (QC). As with any test method considered for inclusion in a regulatory filing, the transition from an ACI (used in development) to an appropriate AIM/EDA methodology (used in QC) should be evaluated and supported by data on a product-by-product basis.
KEY WORDSoral inhaler testing abbreviated impactor measurement mass median aerodynamic diameter efficient data analysis method sensitivity
Andersen cascade impactor (full-resolution, 8-stage)
Abbreviated impactor measurement
Active pharmaceutical ingredient
Aerodynamic particle size distribution
Efficient data analysis
European pharmaceutical aerosol group
Fine particle dose
International pharmaceutical aerosol consortium on regulation and science
Impactor-sized mass (i.e., API mass collected from impactor stages with a defined upper cut-off)
Large particle mass
Mass median aerodynamic diameter
Orally inhaled product
Potential human respiratory tract (when referring to aerosol deposition sites)
Pressurized metered dose inhaler
Root mean square error divided by slope (from regression analysis)
Small particle mass
Total mass (i.e., API mass collected from actuator and all of the impactor stages)
United States pharmacopeia
The authors appreciate support of the IPAC-RS Board of Directors and Cascade Impaction Working Group in conceiving, conducting, and analyzing the study. Special thanks go to the three laboratories that donated their expertise and resources for the study, especially to David Mark (PPD), Michelle Rick (PPD), Cindy Drew (PPD), Kevin Rauschenberger (PPD) and Michael Estrella (BI), Ellen Christman (BI), David Giordano (BI), Jennifer Whitcomb (BI), and Jeffrey Trenck (BI). The authors also thank William Doub for his careful review and thoughtful comments on the draft manuscript, and to Gareth Hardwell, for discussions of early drafts.
- 1.Heyder J, Svartengren MU. Basic principles of particle behavior in the human respiratory tract. In: Bisgaard H, O’Callaghan C, Smaldone GC, editors. Drug delivery to the lung. New York: Marcel Dekker; 2002. p. 21–45.Google Scholar
- 2.FDA, CDER. Draft guidance for industry. metered dose inhaler (MDI) and dry powder inhaler (DPI) drug products chemistry, manufacturing, and controls documentation. 1998. www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm070573.pdf Accessed 31 Mar 2016.
- 6.European Directorate for Quality in Medicines (EDQM). European pharmacopeia 8.0, monograph 2.9.18. Preparations for inhalations: Aerodynamic assessment of fine particles. Strasburg, France EDQM; 2014 (January).Google Scholar
- 7.US Pharmacopeial Convention. United States Pharmacopeia 39/National Formulary 34, Chapter <601> Aerosols, nasal sprays, metered-dose inhalers, and dry powder inhalers. Rockville, MD; 2016.Google Scholar
- 10.Mitchell JP, Tougas T, Christopher JD, Lyapustina S, Glaab V. The abbreviated impactor measurement and efficient data analysis concepts: why use them and when. In: Dalby RN, Byron PR, Peart J, Suman JD, Young PM, editors. Respiratory drug delivery 2012. River Grove: Davis Healthcare International; 2012. p. 731–6.Google Scholar
- 11.Tougas TP, Christopher D, Mitchell JP, Strickland H, Wyka B, Van Oort M, et al. Improved quality control metrics for cascade impaction measurements of orally inhaled drug products (OIPs). AAPS PharmSciTech. 2009;10(4):1276–85.Google Scholar
- 12.Mitchell JP, Nagel MW, Wiersema KJ, Doyle CC. Aerodynamic particle size analysis of aerosols from pressurized metered-dose inhalers: Comparison of Andersen 8-stage cascade impactor, Next Generation pharmaceutical Impactor, and model 3321 Aerodynamic Particle Sizer aerosol spectrometer. AAPS PharmSciTech. 2003;4(4):425–433.Google Scholar
- 13.Mitchell JP, Tougas T, Lyapustina S. The abbreviated impactor measurement (AIM) and effective data analysis (EDA) concepts: why they are important and how to go about working with them. Inhalation. 2012;6(6):13–9.Google Scholar
- 14.European Medicines Agency. Committee for Medicinal Products for Human Use (CHMP). Guideline on the pharmaceutical quality of inhalation and nasal products. EMEA/CHMP/QWP/49313/2005 Corr., London, UK; 2006.Google Scholar
- 15.Copley M, Mitchell JP, Svensson M, Christopher JD, Quiroz J, Daniels G, et al. Validating AIM-based instrumentation and associated measurement techniques. In: Tougas TP, Mitchell JP, Lyapustina SL, editors. Orally inhaled products: good cascade impaction practices, AIM and EDA. N.Y: Springer; 2013. p. 283–358.CrossRefGoogle Scholar
- 16.Mitchell JP, Nagel MW, Doyle C, Ali RS, Avvakoumova V, Christopher D, et al. Relative precision of inhaler aerodynamic particle size distribution (APSD) metrics by full-resolution and abbreviated Andersen cascade impactors (ACIs): part 1. AAPS PharmSciTech. 2010;11(2):843–51. doi: 10.1208/s12249-010-9452-6.CrossRefPubMedPubMedCentralGoogle Scholar
- 17.Mitchell JP, Nagel MW, Doyle C, Ali RS, Avvakoumova V, Christopher D, et al. Relative precision of inhaler aerodynamic particle size distribution (APSD) metrics by full-resolution and abbreviated Andersen cascade impactors (ACIs): part 2—investigation of bias in extra-fine mass fraction with AIM-HRT impactor. AAPS PharmSciTech. 2010;11(3):1115–8. doi: 10.1208/s12249-010-9473-1.CrossRefPubMedPubMedCentralGoogle Scholar
- 18.Mitchell JP, Nagel MW, Avvakoumova V, MacKay H, Ali R. The abbreviated impactor measurement (AIM) concept: part 1—influence of particle bounce and re-entrainment—evaluation with a “dry” pressurized metered dose inhaler (pMDI)-based formulation. AAPS PharmSciTech. 2009;10(1):243–51.CrossRefPubMedPubMedCentralGoogle Scholar
- 19.Nichols S, Sandell D, Mitchell J. A multi-laboratory in vitro study to compare data from abbreviated and pharmacopeial impactor measurements for orally inhaled products: a report of the European Pharmaceutical Aerosol Group (EPAG). AAPS PharmSciTech. 2016; On-line First; doi: 10.1208/S12249-015-0476-9.
- 21.Tougas TP, Goodey AP, Hardwell G, Mitchell J, Lyapustina S. A comparison of the performance of efficient data analysis versus fine particle dose as metrics for the quality control of aerodynamic particle size distributions of orally inhaled pharmaceuticals. AAPS PharmSciTech. 2016; doi: 10.1208/s12249-016-0508-0.
- 22.Christopher D, Dey M, Lyapustina S, Mitchell J, Tougas T, Van Oort M, et al. Generalized simplified approaches for MMAD determination. USP Pharm Forum. 2010;36(3):812–23.Google Scholar
- 23.Christopher D, Quiroz J. Statistical analysis package for the article: ‘Discriminating Ability of Abbreviated Impactor Measurement Approach (AIM) to Detect Changes in Mass Median Aerodynamic Diameter (MMAD) of Inhaler Aerosols’, 2016. http://ipacrs.org/assets/uploads/outputs/Statistical_Supplement_%28IPAC-RS_CIWG_2nd_Expt_Paper%29.pdf. Accessed 16 Dec 2016.
- 24.IPAC-RS. Data package for the article: ‘Discriminating Ability of Abbreviated Impactor Measurement Approach (AIM) to Detect Changes in Mass Median Aerodynamic Diameter (MMAD) of Inhaler Aerosols’, 2016. http://ipacrs.org/assets/uploads/outputs/Data_Supplement_%28%28IPAC-RS_CIWG_2nd_Expt_Paper%29.pdf. Accessed 16 Dec 2016.
- 25.Tougas T, Christopher D, Mitchell J, Lyapustina S, Van Oort M, Bauer R, et al. Product lifecycle approach to cascade impaction measurements. AAPS PharmSciTech. 2011:312–22. doi: 10.1208/s12249-011-9590-5.
- 28.Canavos GC. Applied probability and statistical methods. Boston: Little, Brown and Company; 1984.Google Scholar
- 29.Wheeler DJ, EMP III. (Evaluating the measurement process): using imperfect data. Knoxville: SPC Press; 2006.Google Scholar
- 30.AIAG. Measurement system analysis, Reference manual, 4th Ed., Southfield, MI, USA. ISBN#: 978-1-60-534211-5. June 2010.Google Scholar
- 31.Montgomery D. Introduction to statistical quality control. 6th ed. New York: John Wiley and Sons; 2009.Google Scholar
- 32.Christopher JD, Strickland H, Morgan B, Dey M, Silcock A, Tougas TP, et al. Performance characterization of EDA and its potential to improve decision making in product batch release. In: Tougas TP, Mitchell JP, Lyapustina S, editors. Good cascade impactor practices, AIM and EDA for orally inhaled products. New York: Springer; 2013. p. 173–250.CrossRefGoogle Scholar