Clinically relevant test methods to establish in vitro equivalence for spacers and valved holding chambers used with pressurized metered dose inhalers (pMDIs)

Journal of Aerosol Medicine and Pulmonary Drug Delivery

Volumn 25, Issue 4, 2012, Pages 217-242

  Mitchell, Jolyon ^a   Dolovich, Myrna B ^b  

^a TRUDELL MEDICAL INTERNATIONAL   (Canada)

^b MCMASTER UNIVERSITY   (Canada)

Author keywords

bioequivalence; emitted dose; particle size; regulatory in vitro test procedures; spacers; valved holding chambers

Indexed keywords

GENERIC DRUG; PROPELLANT; SOLVENT;

AEROSOL; AREA UNDER THE CURVE; ASTHMA; BALLISTICS; BIOEQUIVALENCE; BREATHING PATTERN; CANADA; CHRONIC OBSTRUCTIVE LUNG DISEASE; DRUG QUALITY; EUROPE; FACE MASK; FLOW RATE; HUMAN; IN VITRO STUDY; INHALATION SPACER; INSPIRATORY CAPACITY; LABORATORY; LUNG; METERED DOSE INHALER; PARTICLE SIZE; PRACTICE GUIDELINE; RESPIRATORY SYSTEM; REVIEW; STANDARD; STATIC ELECTRICITY; TIDAL VOLUME;

ADMINISTRATION, INHALATION; CANADA; EQUIPMENT DESIGN; HUMANS; MATERIALS TESTING; METERED DOSE INHALERS; PARTICLE SIZE; PHARMACEUTICAL PREPARATIONS; QUALITY CONTROL;

EID: 84864664212     PISSN: 19412711     EISSN: 19412703     Source Type: Journal    
DOI: 10.1089/jamp.2011.0933     Document Type: Review

References (141)

1. European Medicines Agency (EMA): Requirements for clinical documentation for orally inhaled products (OIP) including the requirements for demonstration of therapeutic equivalence between two inhaled products for use in the treatment of asthma and chronic obstructive pulmonary disease (COPD) in adults and for use in the treatment of asthma in children and adolescents. London, UK. CPMP/EWP/4151/00 Rev. 1, 2009. Available at URL: http://www .ema.europa.eu/docs/ en-GB/document-library/Scientific-guideline/2009/09/WC500003504.pdf. Visited September 21, 2011.
2. Health Canada: Release of draft guidance document: Submission requirements for subsequent market entry inhaled corticosteroid products for use in the treatment of asthma. Document 07-118017-24, Ottawa, Canada. Available at URL: http://www.hc-sc.gc.ca/dhp-mps/prodpharma/applic-demande/guide-ld/inhal- corticost-eng.php. Visited September 21, 2011.
3. Parawesmaran K, Leigh R, O'Byrne PM, Kelly MM, Goldsmith CH, Hargreave FE, and Dolovich M: Clinical models to compare the efficacy and safety of inhaled corticosteroids in patients with asthma. Can Respir J. 2003;10:27-34.
4. Rachelefsky GS, Liao Y, and Faruqi R: Impact of inhaled corticosteroid-induced oropharyngeal adverse events: results from a meta-Analysis. Ann Allergy Asthma Immunol. 2007;98:225-238.
5. Barnes NC: The properties of inhaled corticosteroids: similarities and differences. Prim Care Resp J. 2007;16: 149-154.
6. Pedersen S, Dubus JC, and Crompton G: The ADMIT series-Issues in inhalation therapy 5: Inhaler selection in children with asthma. Prim Care Resp J. 2010;19:209-216.
7. Adams WP, Christopher D, Lee DS, Morgan B, Pan Z, Singh GJP, Tsong Y, and Lyapustina S: Product Quality Research Institute evaluation of cascade impactor profiles of pharmaceutical aerosols, Part 1: Background for a statistical method. AAPS PharmSciTech. 2007;8:article 4. Available at: http://www. aapspharmscitech.org/view .asp?art=pt0801004. Visited November 25, 2011.
8. Christopher D, Adams WP, Lee DS, Morgan B, Pan Z, Singh GJP, Tsong Y, and Lyapustina, S: Product Quality Research Institute evaluation of cascade impactor profiles of pharmaceutical aerosols, Part 2: Evaluation of a method for determining equivalence. AAPS PharmSciTech. 2007;8:article 5. Available at: http://www.aapspharmscitech .org/view.asp?art=pt0801005. Visited November 25, 2011.
9. Christopher D, Adams W, Amann A, Bertha C, Byron PR, Doub W, Dunbar C, Hauck W, Lyapustina S, Mitchell J, Morgan B, Nichols S, Pan Z, Singh GJP, Tougas T, Tsong Y, Wolff R, and Wyka B: Product Quality Research Institute evaluation of cascade impactor profiles of pharmaceutical aerosols, Part 3: Final report on a statistical procedure for determining equivalence. AAPS PharmSciTech. 2007;8:article 90. Available at: http://www.aapspharmscitech.org/view.asp?art= pt0804090. Visited November 25, 2011.
10. Newman SP: How well do in vitro particle size measurements predict drug delivery in vivo? J Aerosol Med. 1998; 11:S97-S104.
11. Adams WP, Ahrens RC, Chen M-L, Christopher D, Chowdhury BA, Conner DP, Dalby R, Fitzgerald K, Hendelies L, Hickey AJ, Hochhaus G, Laube BL, Lucas P, Lee SL, Lyapustina S, Li B, O'Connor D, Parikh N, Parkins DA, Peri P, Pitcairn GR, Riebe M, Roy P, Shah T, Singh GJP, Sharp SS, Suman JD, Weda M, Woodcock J, and Yu L: Demonstrating bioequivalence of locally acting orally inhaled drug products (OIPs): workshop summary report. J Aerosol Med Pulm Drug Deliv. 2010;23:1-29.
12. O'Connor D, Adams WP, Chen M-L, Daley-Yates P, Davis J, Derendorf H, Ducharme MP, Fugslang A, Herrle M, Hochhaus G, Holmes SM, Lee SL, Li BV, Lyapustina S, Newman S, Oliver M, Patterson B, Peart J, Poochikian G, Roy P, Shah T, Singh GJP, and Sharp SS: Role of pharmacokinetics in establishing bioequivalence for orally inhaled drug products: workshop summary report. J Aerosol Med Pulm Drug Deliv. 2011;24:119-135.
13. US Code of Federal Regulations: Types of evidence to establish bioavailability or bioequivalence. Code of Federal Regulations Title 21-Food and Drugs. Part 320-Bioavailability and Bioequivalence Requirements, 21 CFR 320.24(b) pp. 183-184, U.S. Government Printing Office. 2010. Available at URL: http://www.access.gpo.gov/nara/cfr/waisidx-03/21cfr320-03.html. Visited September 21, 2010.
14. US Federal Drug Administration. Draft guidance: metered dose inhaler (MDI) and dry powder inhaler (DPI) drug products chemistry, manufacturing and controls documentation. Center for Drug Evaluation and Research. Docket 98D-0997. Rockville, MD. 1998. Available at URL: http://www.fda.gov/downloads/ Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm070573.pdf. Visited September 21, 2011.
15. Becker A, Lemière C, Bérubé D, Boulet L-P, Ducharme FM, FitzGerald M, and Kovesi T: on behalf of the Asthma Guidelines Working Group of the Canadian Network for Asthma Care and the Canadian Thoracic Society. 2005. Summary of recommendations from the Canadian Asthma Consensus Guidelines, 2003, and Canadian Pediatric Asthma Consensus Guidelines. CMAJ. 2003;173(6 suppl.): S1-S56. Available at URL: http://www.canadianmedi caljournal.ca. Visited September 21, 2011.
16. Global Initiative for Asthma (GINA): Global Strategy for Asthma Management and Prevention. December 2010. Available at URL: http://www. ginasthma.com. Visited September 21, 2011.
17. O'Donnell DE, Aaron S, Bourbeau J, Hernandez P, Marciniuk D, Balter M, Ford G, Gervais A, Goldstein R, Hodder R, Maltais F, and Road J: State of the art compendium: Canadian Thoracic Society recommendations for the management of chronic obstructive pulmonary disease. Can Respir J. 2004;11(Suppl.B). Available at URL: http://www.copdguidelines.ca. Visited September 21, 2011.
18. Global Strategy for Diagnosis, Management, and Prevention of Chronic Obstructive Lung Disease (COPD). December 2010. Available at URL: http://www.goldcopd.com.
19. British Thoracic Society/Scottish Intercollegiate Guidance Network (SIGN): British guideline on the management of asthma. Publication 101. September 2011. Available at URL: http://www.sign.ac.uk. Visited September 21, 2011.
20. UK National Institute for Clinical Excellence (NICE): 2000. Guidance on the use of inhaler systems (devices) in children under the age of 5 with chronic asthma. Technology appraisal guidance No.10. Available at URL: http://guidance. nice.org.uk/TA10. Visited September 21, 2011.
21. Mitchell JP, Newman SP, and Chan H-K: In vitro and in vivo aspects of cascade impactor tests and inhaler performance: a review. AAPS PharmSciTech. 2007;8(4):article 110. Available at URL: http://www.aapspharmscitech. org/articles/pt0804/pt0804110/pt0804110.pdf. Visited September 21, 2011.
22. Byron PR, Cummings RH, Nichols SC, Poochikian G, Smurthwaite MJ, Stein SW, and Truman KG: Selection and validation of cascade impactor test methods. In: RN Dalby, PR Byron, J Peart, JD Suman, and SJ Farr, (eds). Respiratory Drug Delivery-IX. Davis Healthcare International Publishing, River Grove, IL; pp. 169-178, 2004.
23. Mitchell JP, and Nagel MW: Spacer and holding chamber testing in vitro: a critical analysis with examples. In: RN Dalby, PR Byron, SJ Farr, and J Peart, (eds). Respiratory Drug Delivery-VII. Serentec Press, Raleigh, NC; pp. 265-273, 2000.
24. Bonam M, Christopher D, Cipolla D, Donovan B, Goodwin D, Holmes S, Lyapustina S, Mitchell J, Nichols S, Petterson G, Quale C, Rao N, Singh D, Tougas T, Van Oort M, Walther B, and Wyka B: Minimizing variability of cascade impaction measurements in inhalers and nebulizers. AAPS PharmSciTech. 2008;9:404-413.
25. Mitchell JP, and Nagel MW: Cascade impactors for the size characterization of aerosols from medical inhalers: their use and limitations. J Aerosol Med. 2003;16:341-377.
26. Rudolph G, Köbrich R, and Stahlhofen W: Modeling and algebraic formulation of regional aerosol deposition in man. J Aerosol Sci. 1990;21(S1):S403-S406.
27. European Medicines Agency (EMA): Guideline on the Pharmaceutical Quality of Inhalation and Nasal Products. London, UK. EMEA/CHMP/QWP/49313/2005 Corr. 2006. Available at URL: http://www.ema.europa.eu/docs/en-GB/document-library/ Scientific-guideline/2009/09/WC500003568.pdf. Visited September 21, 2011.
28. Health Canada (HC): Guidance for Industry: Pharmaceutical Quality of Inhalation and Nasal Products. Document 06-106624-547. Ottawa, Canada. 2006. Available at URL: http://www.hc-sc.gc.ca/dhp-mps/alt-formats/hpfb-dgpsa/pdf/ prodpharma/inhalationnas-eng.pdf. Visited September 21, 2011.
29. US Federal Drug Administration. Reviewer guidance for nebulizers, metered dose inhalers, spacers and actuators. Center for Devices and Radiological Health. Rockville, MD; 1993. Available at URL: http://www.fda.gov/Medical Devices/DeviceRegulationandGuidance/GuidanceDocum ents/ucm081282.htm. Visited September 2, 2011.
30. Mitchell JP, and Nagel MW: Time-of-flight aerodynamic particle size analyzers: their use and limitations for the evaluation of medical aerosols. J Aerosol Med. 1999;12;217-240.
31. Mitchell JP, Nagel MW, Nichols S, and Nerbrink O: Laser diffractometry as a technique for the rapid assessment of aerosol particle size from inhalers. J Aerosol Med. 2006; 19:409-433.
32. Mitchell JP, Bauer R, Lyapustina S, Tougas T, and Glaab V: Non-impactor-based methods for sizing of aerosols emitted from orally inhaled and nasal drug products (OINDPs). AAPS PharmSciTech. 2011:12:965-988. DOI: 10.1208/s12249-011-9662-6. Available at URL: http://www.pharmagateway. net/ArticlePage.aspx?DOI = 10.1208/s12249-011-9662-6. Visited September 23, 2011.
33. Marple VA, Olson BA, Santhanakrishnan K, Mitchell JP, Murray SC, and Hudson-Curtis BL: Next generation pharmaceutical impactor (a new impactor for pharmaceutical inhaler testing)-Part 2: Archival calibration. J Aerosol Med. 2003;16:301-324.
34. European Directorate for the Quality of Medicines and Healthcare (EDQM): European Pharmacopeia 6(8). Chapter 2.9.18. Preparations for inhalations: aerodynamic assessment of fine particles. Strasbourg: Council of Europe; 2010.
35. US Pharmacopeial Convention: United States Pharmacopeia; USP 33-NF 28; Chapter 601-Physical tests and determinations: Aerosols. United States Pharmacopeia, Rockville, MD; 2010.
36. Dolovich MB, Ahrens RC, Hess DR, Anderson P, Dhand R, Rau JL, Smaldone GC, and Guyatt G: Device selection and outcomes of aerosol therapy: evidence-based guidelines. Chest. 2005;127:335-371.
37. Rubin BK, and Fink JB: Optimizing aerosol delivery by pressurized metered-dose inhaler. Respir Care. 2005;50: 1191-1200.
38. Connolly M: Inhaler technique of elderly patients: comparison of metered-dose inhalers and large volume spacer devices. Age Aging. 1995;24:190-192.
39. Dolovich MB: In my opinion: Interview with the expert. Pediatr Asthma Allergy Immunol. 2004;17:292-300.
40. Fink JB: Metered-dose inhalers, dry powder inhalers, and transitions. Respir Care. 2000;45:623-635.
41. Bisgaard H, Anhøj J, and Wildhaber JH: Spacer devices. In: H Bisgaard, C O'Callaghan, and GC Smaldone, (eds). Drug Delivery to the Lung. Marcel Dekker, New York, NY; pp. 389-420, 2000.
42. Thiel GC: From Suzie's question to CFC-free: an inventor's perspective on forty years of MDI development and regulation. In: RN Dalby, PR Byron, and SJ Farr, (eds). Respiratory Drug Delivery-V. Interpharm Press, Buffalo Grove, IL; pp. 115-123, 1996.
43. Corr D, Dolovich M, McCormack D, Ruffin R, Obminski G, and Newhouse M: Design and characteristics of a portable breath actuated, particle size selective medical aerosol inhaler. J Aerosol Sci. 1982;13:1-7.
44. Stein SW: Estimating the number of droplets and drug particles emitted from MDIs. AAPS PharmSciTech. 2008;9:112-115.
45. Dolovich M: Lung dose, distribution, and clinical response to therapeutic aerosols. Aerosol Sci Technol. 1993;18:230-240.
46. Newman SP, Pitcairn GR, and Hirst PH: A brief history of gamma scintigraphy. J Aerosol Med. 2001;14:139-145.
47. Smyth HDC, Hickey AJ, and Evans RM: Aerosol generation from propellant-driven metered dose inhalers. In: AJ Hickey, (ed). Inhalation Aerosols-Physical and Biological Basis for Therapy. Informa Healthcare, New York, NY; pp. 399-416, 2007.
48. Noakes T: Electrostatics: the next issue for inhaled medications. Drug Deliv Technol. 2004;4:1-5.
49. Kwok PKP, and Chan H-K: Electrostatic charge in pharmaceutical systems. In: J Swarbrick, (ed). Encyclopedia of Pharmaceutical Technology, 3rd edition. Marcel Dekker, New York, NY; pp. 1-14, 2006.
50. Barry PW, and O'Callaghan C: The effect of delay, multiple actuations and spacer static charge on the in vitro delivery of budesonide from the Nebuhaler. Br J Clin Pharmacol. 1995;40:76-78.
51. Mitchell JP, and Nagel MW: Valved holding chambers (VHCs) for use with pressurized metered-dose inhalers (pMDIs): a review of causes of inconsistent medication delivery. Prim Care Respir J. 2007;16:207-214.
52. Piérart F, Wildhaber JH, Vrancken I, Devadason SG, and Le Souëf PN: Washing plastic spacers in household detergent reduces electrostatic charge and greatly improves delivery. Eur Respir J. 1999;13:673-678.
53. Rau JL, Coppolo DP, Nagel MW, Avvakoumova VA, Doyle CC, Wiersema KJ, and Mitchell JP: The importance of nonelectrostatic materials in holding chambers for delivery of hydrofluoroalkane albuterol. Respir Care. 2006;51:503-510.
54. Wildhaber JH, Janssens HM, Piérart F, Dore ND, Devadason SG, and LeSouëf PN: High-percentage lung delivery in children from detergent-treated spacers. Pediatr Pulmonol. 2000;29:389-393.
55. Finlay WH: The Mechanics of Inhaled Pharmaceutical Aerosols: An Introduction. Academic Press, London, UK; pp. 19-22, 2001.
56. Bisgaard H: A metal aerosol holding chamber devised for young children with asthma. Eur Respir J. 1995;8:856-860.
57. Bisgaard H, Anhøj J, Klug B, and Berg E: A non-electrostatic spacer for aerosol delivery. Arch Dis Child. 1995;73: 226-230.
58. Cripps A, Riebe M, Schulze M, and Woodhouse R: Pharmaceutical transition to non-CFC pressurized metered dose inhalers. Respir Med. 2000;94(SB):3-9.
59. Leach CT: Enhanced drug delivery through reformulating MDIs with HFA propellants-drug deposition and its effect on preclinical and clinical programs. In: RN Dalby, PR Byron, and SJ Farr, (eds). Respiratory Drug Delivery-V. Interpharm Press Inc., Buffalo Grove, IL; pp. 133-144, 1996.
60. Stein SW: Aiming for a moving target: challenges with impactor measurements of MDI aerosols. Int J Pharm. 2008;355:53-61.
61. Stein SW, and Myrdal PB: The relative influence of atomization and evaporation on metered dose inhaler drug delivery efficiency. Aerosol Sci Technol. 2006;40:335-347.
62. Mitchell JP, Nagel MW, Avvakoumova V, MacKay H, and Ali R: The abbreviated impactor measurement (AIM) concept: Part 2-Influence of evaporation of a volatile component-evaluation with a droplet producing'' pressurized metered dose inhaler (pMDI)-based formulation containing ethanol as co-solvent. AAPS PharmSciTech. 2009;10:252-257.
63. Mitchell JP, Nagel MW, MacKay HA, Avvakoumova VA, and Malpass J: Developing a universal'' valved holding chamber (VHC) platform with added patient benefits whilst maintaining consistent in vitro performance. In: RN Dalby, PR Byron, J Peart, JD Suman, and PM Young, (eds). Respiratory Drug Delivery Europe 2009. Davis Healthcare International Publishing, River Grove, IL; pp. 383-386, 2009.
64. Dolovich M: Characterization of medical aerosols: physical and clinical requirements for new inhalers. Aerosol Sci Technol. 1995;22:392-399.
65. Harrison L: Aerosol therapy: the practicalities. Proceedings of the Second World Equine Airways Symposium, Scotland 2001, International Veterinary Information Service (IVIS). Available at URL: http://www.ivis.org/proceedings/ weas/2001/Harrison.pdf. Visited June 30, 2011.
66. Nagel MW, Wiersema KJ, Bates SL, and Mitchell JP: Size analysis of a pressurized metered dose inhaler-delivered solution formulation by an Aerosizer-LD time-of-flight aerosol particle size spectrometer. J Aerosol Med. 2002; 15:75-85.
67. Leach CT, and Colice GL: A pilot study to assess lung deposition of HFA-beclometasone and CFC-beclometasone from a pressurized metered dose inhaler with and without add-on spacers and using varying breathhold times. J Aerosol Med Pulm Drug Deliv. 2010;23:355-361.
68. Leach C, Davidson PJ, and Boudreau RJ: Improved airway targeting with the CFC-free HFA-beclomethasone metered-dose inhaler compared with CFC-beclomethasone. Eur Respir J. 1998;12:1346-1353.
69. Hochhaus G: New developments in corticosteroids. Proc Am Thorac Soc. 2004;1:269-274.
70. Rahmattala MF, Zuberbuhler PC, Lange CF, and Finlay WH: In Vitro effect of a holding chamber on the mouththroat deposition of QVAR- (hydrofluoroalkane- beclometasone dipropionate). J Aerosol Med. 2002;15:379-385.
71. Stapleton KW, Guentsch E, Hoskinson MK, and Finlay WH: On the suitability of K-e turbulence modeling for aerosol deposition in the mouth and throat: a comparison with experiment. J Aerosol Sci. 2000;31:739-749.
72. Newman SP, Pavia D, and Clarke SW: How should a pressurized beta-Adrenergic bronchodilator be inhaled? Eur J Respir Dis. 1981;62:3-21.
73. Laube BL, Edwards AM, Dalby RN, Creticos PS, and Norman PS: The efficacy of slow versus faster inhalation of cromolyn sodium in protecting against allergen challenge in patients with asthma. J Allergy Clin Immunol.1998; 101:475-483.
74. Cheng YS, Fu CS, Yazzie D, and Zhou Y: Respiratory deposition patterns of salbutamol pMDI with CFC and HFA-134a formulations in a human airway replica. J Aerosol Med. 2001;14:255-266.
75. Dolovich M, MacIntyre NR, Anderson PJ, Camargo CA, Chew N, Cole CH, Dhand R, Fink JB, Gross NJ, Hess DR, Hickey AJ, Kim CS, Martonen TB, Pierson DJ, Rubin BK, and Smaldone GC: Consensus statement: aerosols and delivery devices. Respir Care. 2000;45:589-596.
76. Charan NB, Turk GM, and Dhand R: Gross and subgross anatomy of bronchial circulation in sheep. J Appl Physiol. 1984;57:658-664.
77. Chrystyn H: Methods to identify drug deposition in the lungs following inhalation. Br J Clin Pharmacol. 2001; 51:289-299.
78. Lipworth BJ, and Clark DJ: Early lung absorption profile of non-CFC salbutamol via small and large volume plastic spacer devices. Br J Clin Pharmacol. 1998;46:45-48.
79. Silkstone VL, Tomlinson HS, Corbett SA, and Chrystyn H: Relative bioavailability of salbutamol to the lung following inhalation when administration is prolonged. Br J Clin Pharmacol. 2000;50:281-284.
80. Borgström L, Bengtsson T, Derom E, and Pauwels R: Variability in lung deposition of inhaled drug, within and between asthmatic patients, with a pMDI and a dry powder inhaler, Turbuhaler-. Int J Pharm. 2000;193:227-230.
81. Lipworth BJ: Pharmacokinetics of inhaled drugs. Br J Clin Pharmacol. 1996;42:697-705.
82. Ahrens RC: The role of the MDI and DPI in pediatric patients: Children are not just miniature adults''. Respir Care. 2005;50:1323-1330.
83. Newman SP, and Chan H-K: In vitro/in vivo comparisons in pulmonary drug delivery. J Aerosol Med. 2008;21:1-8.
84. Borgström L, Asking L, Beckman O, Bondesson E, Källén A, and Olsson B: Dose variation, within and between individuals, with different inhalation systems. In: RN Dalby, PR Byron, and SJ Farr, (eds). Respiratory Drug Delivery V. Interpharm Press, Buffalo Grove, IL; pp. 19-24, 1996.
85. Ehtezazi T, Saleem I, Shrubb I, Allanson ID, and O'Callaghan C: The interaction between the oropharyngeal geometry and aerosols via pressurized metered dose inhalers. Pharm Res. 2010;27:175-186.
86. Ehtezazi T, Allanson DR, Jenkinson ID, and O'Callaghan C: Effect of oropharyngeal length in drug delivery via suspension pressurized metered dose inhalers. Pharm Res. 2006;23:1364-1372.
87. Dolovich M, and Rhem R: Impact of oropharyngeal deposition on inhaled dose. J Aerosol Med. 1998;11(S1):S112-S115.
88. Dissanayake S: Application of the EU guidelines for pharmacokinetic studies of locally acting orally inhaled drug products. In: RN Dalby, PR Byron, J Peart, JD Suman, SJ Farr, and PM Young, (eds). Respiratory Drug Delivery 2010. Davis Healthcare International Publishing, River Grove, IL; pp. 293-304, 2010.
89. Health Canada: Release of draft guidance document: Data requirements for safety and effectiveness of subsequent market entry inhaled corticosteroid products for use in the treatment of asthma, for industry. Document 11-116649-777, Ottawa, Canada, released September 19, 2011. Available at URL: http://www.hc-sc.gc.ca/dhp-mps/prodpharma/applic-demande/guide-ld/ inhal-corticost-eng.php. Visited November 28, 2011.
90. Barry PW, and O'Callaghan C: In vitro comparison of the amount of salbutamol available for inhalation from different formulations used with different spacer devices. Eur Respir J. 1997;10:1345-1348.
91. Dubus J-C, Rhem R, and Dolovich M: Delivery of HFA and CFC salbutamol from spacer devices used in infancy. Int J Pharm. 2001;222:101-108.
92. Ahrens R, Lux C, Bahl T, and Han S: Choosing the metereddose inhaler spacer or holding chamber that matches the patient's need: evidence that specific drug being delivered is an important consideration. J Allergy Clin Immunol. 1995;96:288-294.
93. Barry PW, and O'Callaghan C: A comparative analysis of the particle size output of beclomethasone dipropionate, salmeterol xinafoate and fluticasone propionate metered dose inhalers used with the Babyhaler, Volumatic and AeroChamber spacer devices. Br J Clin Pharmacol. 1999; 47:357-360.
94. Rau JL, Coppolo DP, Nagel MW, Avvakoumova VA, Doyle CC, Wiersema KJ, and Mitchell JP: The importance of nonelectrostatic materials in holding chambers for delivery of hydrofluoroalkane albuterol. Respir Care. 2006;51: 503-510.
95. Lavorini F, Fontana G, and Pistolesi M: Drug Delivery to the Lungs-Effects of Spacer Devices. Touchbriefings Pediatric Healthcare-Respiratory Health. European Special Populations 2006;8-12. Available at URL: http://www .touchbriefings.com/F227D793-1B40-4117-8A88-3DDAB37 D4AE7/FinalDownload/ DownloadId-985EA696858B7C472E1CCB27E1001B40/F227D793-1B40-4117-8A88- 3DDAB37D4AE7/pdf/2386/Lavorini.pdf. Visited November 30, 2011.
96. Roller CM, Zhang G, Troedson RG, Leach CL, Le Souëf PN, and Devadason SG: Spacer inhalation technique and deposition of extrafine aerosol in asthmatic children. Eur Respir J. 2007;29:299-306.
97. Dolovich M: Aerosol delivery to children: what to use, how to choose. Pediatr Pulmonol. 1999;Suppl.18:79-82.
98. Schultz A, Le Souëf TJ, Looi K, Zhang G, Le Souëf PN, and Devadason SG: Validation of methodology for recording breathing and simulating drug delivery through spacers and valved holding chambers. J Aerosol Med Pulm Drug Deliv. 2010;23:311-322.
99. Bosco AP, Rhem R, and Dolovich MB: In vitro estimations of in vivo jet nebulizer efficiency using actual and simulated tidal breathing patterns. J Aerosol Med. 2005;18:427-438.
100. Mitchell JP, Nagel MW, Wiersema KJ, Bates SL, Morton RW, and Schmidt JN: Performance of large and small volume valved holding chambers (VHCs) as a function of flow rate. [Abstract] Drug Delivery to the Lungs-XI. The Aerosol Society, London, UK. 2000, pp. 52-55, in J Aerosol Med. 2001;14:122.
101. Marple VA, Olson BA, Santhanakrishnan K, Mitchell JP, Murray SC, and Hudson-Curtis BL: Next generation pharmaceutical impactor (a new impactor for pharmaceutical inhaler testing)-Part III: Extension of archival calibration to 15 L/min. J Aerosol Med. 2004;17: 335-343.
102. Olson BA, Marple VA, Mitchell JP, and Nagel MW: Development and calibration of a low-flow version of the Marple-Miller impactor. Aerosol Sci Technol. 1998;29:307-314.
103. Marple VA, and Liu BYH: Characteristics of laminar jet impactors. Environ Sci Technol. 1974;8:648-654.
104. Foss SA, and Keppel JW: In vitro testing of MDI spacers: a technique for measuring respirable dose output with actuation in-phase or out-of-phase with inhalation. Respir Care. 1999;44:1474-1485.
105. Finlay WH: Inertial sizing of aerosol inhaled during pediatric tidal breathing from an MDI with attached holding chamber. Int J Pharm. 1998;168:147-152.
106. Brindley A, Marriott RM, Sumby BS, and Smith IJ: The electronic lung: a novel tool for the characterization of inhalation devices. J Pharm Pharmacol. 1994;45:1-35.
107. Canadian Standards Association: Spacers and holding chambers for use with metered-dose inhalers. Mississauga, ON, Canada. CAN/CSA/Z264.1-02: 2002, revised 2008. Available at URL: http://shop.csa.ca/en/canada/druglabeling-And- delivery/cancsa-z2641-02-r2008/invt/27017422002/. Visited September 1, 2011.
108. Dolovich M, and Rhem R: Impact of oropharyngeal deposition on inhaled dose. J Aerosol Med. 1998;11(S1):112-115.
109. Stapleton KW, Guentsch E, Hoskinson MK, and Finlay WH: On the suitability of k-turbulence modeling for aerosol deposition in the mouth and throat: a comparison with experiment. J Aerosol Sci. 2000;31:731-749.
110. Grgic B, Finlay WH, and Heenan, AF: Regional aerosol deposition and flow measurements in an idealized mouth and throat. J Aerosol Sci. 2004;35:21-32.
111. Copley M, Mitchell J, and Solomon D: Evaluating the Alberta throat: an innovation to support the acquisition of more clinically applicable aerosol aerodynamic particle size distribution (APSD) data in oral inhaled product (OIP) development. Inhalation. 2011;5(4):12-16.
112. Mitchell J, Copley M, Sizer Y, Rusell T, and Solomon D: Adapting the abbreviated impactor measurement (AIM) concept to make appropriate inhaler aerosol measurements to compare with clinical data: a scoping study with the Alberta'' idealized throat inlet. J Aerosol Med Pulm Drug Deliv. 2012 (in press).
113. Stocks J, and Hislop AA: Structure and function of the respiratory system. In: H Bisgaard, C O'Callaghan, and GC Smaldone, (eds). Drug Delivery to the Lung. Marcel Dekker Inc., New York, NY; pp. 47-104, 2002.
114. Mitchell JP, and Nagel MW: In vitro performance testing of three small volume valved holding chambers under conditions that correspond with use by infants and small children. J Aerosol Med. 1997;10:341-349.
115. Richards J, Hirst P, Pitcairn G, Mahashabde S, Abramowitz W, Nolting A, and Newman SP: Deposition and pharmacokinetics of flunisolide delivered from pressurized inhalers containing non-CFC and CFC propellants. J Aerosol Med. 2001;14:197-208.
116. Christopher D, Curry P, Doub W, Furnkranz K, Lavery M, Lin K, Lyapustina S, Mitchell J, Rogers B, Strickland H, Tougas T, Tsong Y, and Wyka B: Considerations for the development and practice of cascade impaction testing including a mass balance failure investigation tree. J Aerosol Med. 2003;16:235-247.
117. International Society for Aerosols in Medicine (ISAM)/International Pharmaceutical Aerosol Consortium on Regulation and Science (IPAC-RS): Equivalence Considerations EU Workshop, Frankfurt-Am-Main, Germany. October 12-13, 2010. Presentations available at: http://www .ipacrs.com/beworkshop.html. Visited September 21, 2011.
118. Dolovich MB, and Mitchell JP: Canadian Standards Association standard CAN/CSA/Z264.1-02:2002: A new voluntary standard for spacers and holding chambers used with pressurized metered-dose inhalers. Can Respir J. 2004;11:489-495.
119. Bernstein JA, Amin H, and Smith SJ: Therapeutic uses of lung aerosol. In: AJ Hickey, (ed). Inhalation Aerosols: Physical and Biological Basis for Therapy. Informa Healthcare, New York, NY; pp. 219-252, 2007.
120. Newman SP: Inhaler treatment options in COPD. Eur Respir Rev. 2005;14:96:102-108.
121. Boulet L-P, Becker A, Bérubé D, Beveridge R, and Ernst P, on behalf of the Canadian Asthma Consensus Group: Canadian asthma consensus report, 1999. CMAJ. 1999;161(11 Suppl):S1-S62.
122. Chapman KR, Voshaar TH, and Virchow JC: Inhaler choice in primary practice. Eur Respir Rev. 2005;14:96:117-122.
123. Crompton GK: How to achieve good compliance with inhaled asthma therapy. Respir Med. 2004;98:S35-S40.
124. Hidinger KG, and Perk J: Clinical trial of a modified inhaler for pressurized aerosols. Eur J Clin Pharmacol. 1981;20: 109-111.
125. Demirkan K, Tolley E, Mastin T, Soberman J, Burbeck J, and Self T: Salmeterol administration by metered-dose inhaler alone vs. metered-dose inhaler plus valved holding chamber. Chest. 2000;117:1314-1318.
126. Mitchell JP, Bates SL, Doyle CC, and Nagel MW: Comparison of performance of two valved holding chambers (VHCs) at flow rates appropriate for simulating pediatric use. Respir Care. 2002;47:1074.
127. International Standards Organization: Aerosol drug delivery device design verification-requirements and test methods. Geneva, Switzerland. ISO 20072:2009. Available at: http://www.iso.org/iso/catalogue-detail.htm?csnumber= 41989. Visited September 21, 2011.
128. Shah SA, Berlinski A, and Rubin BK: Force-dependent static dead space of face masks used with holding chambers. Respir Care. 2006;51:140-144.
129. Amirav I: Infant aerosol holding chamber face masks: not all are born equal! Respir Care. 2006;51:123-125.
130. Esposito-Festen JE, Ates B, Van Vliet FLM, Verbraak AFM, de Jongste JC, and Tiddens HAWM: Effect of a facemask leak on aerosol delivery from a pMDI-spacer system. J Aerosol Med. 2004;17:1-6.
131. Smaldone GC, Berg E, and Nikander K: Variation in pediatric aerosol delivery: importance of facemask. J Aerosol Med. 2005;18:354-363.
132. Amirav I, and Newhouse MT: Dead space variability of face masks for valved holding chambers. Isr Med Assoc J. 2008;10:224-226.
133. Finlay WH: Inertial sizing of aerosol inhaled during pediatric tidal breathing from an MDI with attached holding chamber. Int J Pharm. 1998;168:147-152.
134. Mitchell JP, Wiersema KJ, MacKay HA, Nagel MW, Pischel SM, and Cripps AL: Novel approach for evaluating medication delivered via valved holding chambers (VHCs) with facemask using a face model for infants and small children. In: RN Dalby, PR Byron, J Peart, JD Suman, SJ Farr, and PM Young, (eds). Respiratory Drug Delivery 2008. Davis Healthcare International Publishing, River Grove, IL; pp. 785-788, 2008.
135. Janssens HM, De Jongste JC, Fokkens WJ, Robben SGF, Wouters K, and Tiddens HAWM: The Sophia anatomical infant nose-throat (Saint) model: a valuable tool to study aerosol deposition in infants. J Aerosol Med. 2001;14:433-441.
136. Mitchell JP: Appropriate face models for evaluating drug delivery in infants and small children: the current situation and prospects for future advances. J Aerosol Med. 2008; 21:97-111.
137. Mitchell JP, Finlay JB, Nuttall JM, Limbrick M, Nagel MW, Avvakoumova VI, MacKay HA, Ali RS, and Doyle CC: Validation of a new model infant face with nasopharynx for the testing of valved holding chambers with facemask as a patient interface. In: RN Dalby, PR Byron, J Peart, JD Suman, SJ Farr, and PM Young, (eds). Respiratory Drug Delivery 2010. Davis Healthcare International Publishing LLC, River Grove, IL; pp. 777-780, 2010.
138. Mitchell JP, Nagel M, and Finlay B: Advances in models for laboratory testing of inhalers: there's more to it than meets the nose or mouth-The ADAM face models. In: RN Dalby, PR Byron, J Peart, JD Suman, SJ Farr, and PM Young, (eds). Respiratory Drug Delivery Europe 2011. Davis Healthcare International Publishing LLC, River Grove, IL; pp. 457-461, 2011.
139. Mitchell JP, Poochikian G, Hickey AJ, Suggett J, Curry P, and Tougas T: In vitro assessment of spacers and valved holding chambers used with pressurized metered-dose inhalers: the need for a USP chapter with clinically relevant test methods. Pharm Forum. 2011;37(4) online at: http://www.usppf.com/pf/pub/index. html. Visited September 21, 2011.
140. Parameswaran K, Leigh R, O'Byrne PM, Kelly MM, Goldsmith CH, Hargreave FE, and DolovichM: Clinical models to compare the safety and efficacy of inhaled corticosteroids in patients with asthma. Can Respir J. 2003;10:27-34.
141. Dolovich M: Airway delivery devices and airways/lung deposition. In: R Schleimer, PM O'Byrne, S Szefler, and R Brattsand, (eds). Inhaled Steroids in Asthma. Marcel Dekker, New York, NY; pp. 169-212, 2002.