title: Considerations for Designing In Vitro Bioequivalence (IVBE) Studies for Pressurized Metered Dose Inhalers (pMDIs) with Spacer or Valved Holding Chamber (S/VHC) Add-on Devices.
abstract: BACKGROUND
  The choice of analytical test methods and associated statistical considerations are considered for the laboratory testing of pressurized metered dose inhaler-spacer/valved holding chamber (pMDI-S/VHC) combinations for in vitro bioequivalence (IVBE).
  
  
  METHODS
  Four scenarios are presented for comparing TEST ("second entry" or "generic") versus REF ("innovator"): (1) innovator and second entry product pMDI alone without any S/VHC (baseline comparison); (2) innovator and second entry pMDI product with the same S/VHC; (3) innovator pMDI product with existing S/VHC and second entry product with a different S/VHC; and (4) introduction of a second, different S/VHC to be used with a given innovator pMDI product. The following aspects should be reviewed in the preparatory stage of designing experiments to establish IVBE: (a) the inclusion of delayed inhalation; (b) the utilization of age-appropriate flow rates; and (c) the use of anatomically appropriate face models for evaluation of devices with a facemask. Statistical considerations that fit in with such experimental methods include: selection of pMDI batches and S/VHC lots; choice of sample size and acceptance criteria; bracketing or worst case approaches; and balanced/paired designs. A stepwise approach for selection of impactor stage groupings is presented, and an approach to determine realistic acceptance criteria based on REF product characteristics is suggested.
  
  
  RESULTS
  An example of an efficient statistical design of experiment is provided for each scenario, together with alternate approaches for calculation of confidence intervals for the mean TEST/REF relationship. It is important to appreciate that the optimal design depends on balancing numerous considerations and will thus likely differ from case to case; hence, the designs presented here should be seen as illustrations rather than the only option available. More effective approaches may be found that suit a particular case at hand.
  
  
  CONCLUSIONS
  The information provided will assist in developing correlations in support of IVBE for these add-on devices.
authors.affiliation: 1S5 Consulting, Blentarp, Sweden.
authors.forename: Dennis
authors.initials: D
authors.lastname: Sandell
authors.affiliation: 2Jolyon Mitchell Inhaler Consulting Services Inc., London, ON, Canada.
authors.forename: Jolyon P
authors.initials: JP
authors.lastname: Mitchell
mesh_terms: D000280:Administration, Inhalation; D000336:Aerosols; D000367:Age Factors; D058868:Compressed Air; D018795:Device Approval / Q000592:standards; D004867:Equipment Design; D005060:Europe; D005145:Face / Q000033:anatomy & histology; D017408:Guidelines as Topic; D006801:Humans; D036503:Inhalation Spacers / Q000592:standards; D008422:Materials Testing / Q000379:methods* / Q000592:standards; D036501:Metered Dose Inhalers / Q000592:standards; D008953:Models, Anatomic; D015233:Models, Statistical; D004364:Pharmaceutical Preparations / Q000008:administration & dosage* / Q000737:chemistry; D011786:Quality Control; D012107:Research Design / Q000592:standards; D013810:Therapeutic Equivalency; D014481:United States; D014486:United States Food and Drug Administration
chemical_list: D000336:Aerosols; D004364:Pharmaceutical Preparations
keywords: experiment design; in vitro bioequivalence; inhaler testing; pMDI; spacer; statistical methods; valved holding chamber