EPAG Sponsored Workshop on Abbreviated Impactor Measurement (AIM) and Efficient Data Analysis (EDA) Concepts in Inhaler Testing. Overview of AIM EDA

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1 EPAG Sponsored Workshop on Abbreviated Impactor Measurement (AIM) and Efficient Data Analysis (EDA) Concepts in Inhaler Testing Overview of AIM EDA Jolyon Mitchell 1 and Mark Copley 2 1 Trudell Medical International (TMI), London, Canada 2 Copley Scientific Ltd., Nottingham, UK AIM Workshop 1

2 INTRODUCTION AIM most recent version developed 4 years agoatat TMI in order to improve operating efficiency of a small aerosol laboratory Simplify the multi stage cascade impactor (CI) to the minimum required to determine relevant metrics related to inhaler aerosol aerodynamic particle size distribution (APSD) Has since grown into a major initiative throughout h our industry AIM Workshop 2

3 UNDERLYING PRINCIPLE OF AIM The cascade impactor is NOT a lung simulator However, it DOES determine APSD from which pertinent size sub fractions may be obtained. The handling of these sub fractions is at the heart of EDA ICRP 66 lung deposition sub fractions compared with stage collection efficiency curves for the Andersen 8 stage CI: Mitchell & Dunbar JAM 2005;18(4): AIM Workshop 3

4 EFFICIENT DATA ANALYSIS Not the main focus of this Workshop, but an important development that has helped make AIM more viable Two mutually independent metrics, small (SPM) and large particle (LPM) mass Impactor sized mass (ISM) encompasses the measured APSD Metric 1: LPM + SPM = ISM Metric 2: LPM/SPM AIM Workshop 4

5 AIM HAS 2 DISTINCT PATHWAYS FULL RESOLUTION CI MEASUREMENTS AIM MEASUREMENTS PRODUCT QC HRT RELEVANT APPLICATIONS SPM, LPM EPM, FPM, CPM MMAD, SPM, LPM EDA METRICS HRT METRICS REFERENCE TECHNIQUE Better decision making tool than grouped CI stages Appropriate in support of IVIVRs: Likely use anatomically correct inlet AIM Workshop 5

6 MANY AIM APPARATUS POSSIBILITIES Twin Impinger Copley Fast Screening Andersen (FSA) FSA with inoperative Stage 0 for aerosols with low volatile species MSP Fast Screening Impactor (FSI) Westech FPD Impactor Abbreviated NGI AIM Workshop 6

7 AIM EXPERIMENTS AT TMI Two major campaigns: : Assess viability of approach with two abbreviated ACI designs Copley FSA (C FSA) In house FSA with inactive stage 0 (T FSA) : Undertake a designed experiment on behalf of IPAC RS to assess precision and accuracy of two ACI designs QC impactor HRT impactor AIM Workshop 7

8 CAMPAIGN 1: C FSA C FSA is two stage stack that divides the incoming dose into coarse, fine and extra fine fractions (CPF, FPF and EPF, respectively) The C FSA was operated with stage cut off diameters of 4.7 and 1.0 microns at 28.3 L/min Other cut off combinations are possible AIM Workshop 8

9 T FSA was developed at TMI, andhasstage stage cut off diameters of 4.7 and 1.1 microns at 28.3 L/min, for direct comparison with stages 2 and 5 of the full resolution ACI It also includes a nonoperable (collection surface removed) ACI stage 0 to provide functional dead space before the first size separating stage CAMPAIGN 1: T FSA AIM Workshop 9

10 CAMPAIGN 1: Methods STUDY μg/actuation pmdi delivering dry fluticasone propionate particles in HFA 134 propellant: Mitchell, JP et al. AAPS PharmSciTechnol., 2009, 10(1), STUDY μg/actuation pmdi delivering beclomethasone dipropionate particles with ethanol co solvent (8% v/v) in HFA 134 propellant: Mitchell et al. AAPS PharmSciTechnol., 2009, 10(1), AIM Workshop 10

11 CAMPAIGN 1 STUDY 1: Findings It was essential to coat collection surfaces with an agent to prevent particle bounce and re entrainment biasing FPF to larger values uncoated surfaces We used Brij 35 polyoxyethylene 23 lauryl ether surfactant, but alternatives are likely to be equally as good Brij 35 coated surfaces AIM Workshop 11

12 CAMPAIGN 1 STUDY 2: Findings The additional functional space afforded d by the inactive stage 0 was needed to match ethanol evaporation with full resolution ACI Closer agreement between FPF from full resolution ACI when Inactive stage 0 was present Liquid ethanol sensitive paper showing presence of liquid phase on upper stage when inactive stage 0 was NOTpresent AIM Workshop 12

13 CAMPAIGN 2: IPAC RS EXPERIMENT Measurements e e s with HFAsalbutamol (100 μg/actuation) / i ) from narrow time slit in batch manufacture Design minimized sources of bias AIM Workshop 13

14 IPAC RS EXPERIMENT: Methods See Mitchell JP et al. AAPS PharmSciTechnol., 2010; 11(2): days of expensive measurements using 3 trained operators Near to optimum working conditions AIM Workshop 14

15 IPAC RS EXPERIMENT: Findings IM and ISM were highly correlated with IM> ISMby ca. 1 μg/actuation IM includes stage 0 for ACI needed for comparisons with AIM HRT system Ratio LPM/SPM by AIM QC system equivalent to full ACI FPM by AIM HRT system equivalent to full ACI The experiment was a success! AIM Workshop 15

16 FOLLOW ON ON STUDY EPM from the AIM phrt was higher than with the ACI Cause was residual particle bounce eliminated by use of Brijkdfl filter on stage 2 of C ll i l soaked Showing HRT system See: Mitchell et al. AAPS PharmSciTechnol., 2010;11(3): OnLine First Collection plate displacement of surfactant by flow through stage 2 of AIM HRT system AIM Workshop 16

17 CONCLUDING REMARKS These proof of conceptof experiments provided the basis for developing the AIM Concept into a formal approach for characterizing OIP aerosols However more work is needed to be done with otherinhalerformats with the systems available The remainder of this workshop is devoted to examination of data covering all types of OIP, undertaken by a variety of organizations inside and beyond EPAG AIM Workshop 17