Good Cascade Impactor Practices
The CI-based methods for measuring the APSD properties of OIP-produced aerosols are complex, exacting, and laborious to undertake. Yet they are the only accepted methods by regulatory agencies worldwide for determining particle aerodynamic size-related p
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Good Cascade Impactor Practices Jolyon P. Mitchell
Abstract The CI-based methods for measuring the APSD properties of OIP- produced aerosols are complex, exacting, and laborious to undertake. Yet they are the only accepted methods by regulatory agencies worldwide for determining particle aerodynamic size-related properties. In 2003, a group within the Product Quality Research Institute (PQRI), a body set up by pharmaceutical industry, the FDA, and academia to explore complex scientific and regulatory problems, developed a guide to good cascade impactor practices (GCIP). This chapter contains a review of the essence of their work, augmented by developments that have taken place since the original article was published.
4.1 Intrinsic Variability Associated with CI Methodologies The multistage CI is well known to be both a complex and labor-intensive a pparatus, whatever compendial variant is used in OIP aerosol aerodynamic particle size assessment. In discussions within the European Pharmaceutical Aerosol Group (EPAG) following the development of the NGI, the comment was made on several occasions that a technician, well trained in the “art” of cascade impaction is highly sought after and difficult to replace. More seriously, the difficulty in replicating CI measurements undertaken in the same laboratory or when transferring a method to another laboratory is a significant hindrance to both OIP development and quality control processes. In 2004, Nichols reported a survey of members of the EPAG in connection with what they viewed as contributors to variability in CI-based measurements [1]. These estimates of causes of measurement variability that were based on individual experience rather than a formal work study and statistical analysis
J.P. Mitchell (*) Trudell Medical International, 725 Third Street, London, ON N5V 5G4, Canada e-mail: [email protected] T.P. Tougas et al. (eds.), Good Cascade Impactor Practices, AIM and EDA for Orally Inhaled Products, DOI 10.1007/978-1-4614-6296-5_4, © Springer Science+Business Media New York 2013
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Fig. 4.1 Five principal causes of nonhuman factor-related CI method variability, showing their contribution to the overall variability of the method (Adapted from [1]—used by permission)
(Fig. 4.1) are probably unsurprising. Not considering human-related factors, airflow and laboratory e nvironmental controls were estimated to contribute ±10% of total variability between them, followed by impactor geometry causes (mainly nozzle size control) at ±2%, and finally internal losses in the CI providing ±2% to the measures of OIP performance. CI-related contributors were only part of the overall measurement variability process, with a further ±20% estimated to come from the inhaler itself in the form of actuation-to-actuation reproducibility through life, as well as a contribution e stimated to be ±3% from the recovery and assay of the API.
4.2 A ssessment of Factors Contributing to CI Measurement Variability Bonam et al. [2], in a comprehensive revi
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