Optimising Mixing Process Parameters for an HFA pMDI Dual Suspension Product During Early Phase Product Development

Sarah Dexter

3M UK Ltd, Morley Street, Loughborough, Leics, LE11 1EP, UK

Summary

This study highlights the importance of investigating mixing parameters used during the manufacture of suspension pressurised metered dose inhalers (pMDIs) containing hydrofluoroalkanes (HFA).  Two critical process parameters were evaluated; mixer speed and mixing time, and their impact on drug content assay and fine particle mass (FPM) were shown to be significant for a dual suspension pMDI containing ipratropium bromide monohydrate (IBM) and albuterol (A).  Furthermore, the data highlighted that achieving the target drug content assay in a pMDI product is not always an appropriate indicator of optimal mixing.

For both active pharmaceutical ingredients (API) a mixing speed of 7000 rpm was required for a minimum of five minutes to produce a formulation that delivered the target FPM.  This was despite the drug content assay data suggesting that formulations were adequately mixed at lower speeds (4000 rpm) and shorter mixing times.

Adopting a quality by design (QbD) approach to mixing is recommended at the earliest phase of an HFA pMDI product development to generate product understanding and to determine a design space with respect to mixing parameters and their effect on product critical quality attributes, namely aerodynamic particle size distribution (APSD) and FPM.  This is particularly important when developing generic products, where matching the in-vitro pharmaceutical performance of a reference product may be required.