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.

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.