Jolyon P. Mitchell

Validating AIM-Based Instrumentation and Associated Measurement Techniques

The validation of the wide variety of equipment capable of making abbreviated impactor measurements is a key component providing proof that the AIM concept works in practice. This chapter provides a comprehensive collection of validation experiments that have been provided by a variety of different laboratories, mainly through the support of the Cascade Impactor sub-team of the European Pharmaceutical Aerosol Group (EPAG), who held a Workshop on the topic in December 2010. These studies have involved the whole range of OIP formats, thereby increasing confidence in the wide applicability of the approach. A series of “learnings” are summarized at the end of the chapter as guidance for those planning on implementing an AIM-based method.

Current Approaches to APSD Measurements of OIPs Based on Inertial Impaction

The AIM and EDA concepts are founded on the principles of inertial impaction of aerosol particles under laminar flow conditions. This chapter examines the current CI systems that are recognized by the pharmaceutical compendia, providing a summary of the key parameters that affect the size-resolving capability of each system. The potential for bias introduced through the assumption that individual stage collection efficiency curves are step functions at the calibration size is explored, with attention given to the effect of removing stages in order to achieve an AIM-based configuration. Non-sizing accessories, such as the induction port (IP) entry and preseparator (PS), are discussed and the chapter concludes with consideration of how add-on devices, such as spacers and VHCs that are commonly used in conjunction with MDIs, should be evaluated.

Experimental Assessment and Calibration of an Inertial Spectrometer

An experimental assessment has been made of the performance of an inertial spectrometer to measure the aerodynamic diameter of aerosol particles. These studies have included a determination of the optimum operating conditions for good size resolution, and the calibration of the instrument with monodisperse aerosol particles. Sampling conditions had to be chosen with care in order to ensure that the instrument operated correctly and separated particles on the basis of their aerodynamic size. When the instrument was upright, the calibration curves agreed closely with those of the manufacturer. However, when the spectrometer was inverted, the calibration curves were slightly displaced due to the change in direction of the gravitational force with respect to the other forces acting on the particles as they passed through the spectrometer.

Spatial aerosol flow maldistribution: A design flaw confounding the proper calibration and data interpretation of stages “0” and “1” of the Andersen eight-stage nonviable cascade impactor

ABSTRACT We introduced monodisperse calibrant particles into an eight-stage non-viable Andersen cascade impactor (ACI) operated at 28.3 L/min and separately quantified the particle mass captured under each of the four concentric rings of nozzles on stages 0 and 1, the entry and succeeding stages of this impactor. On both stages, we found that each ring of nozzles has a particle capture efficiency behavior that differs from the others, and the fraction of calibrant particles deposited under each of the individual rings of nozzles depended on the particle size. We believe this behavior derives primarily from a radial flow velocity non-uniformity associated with recirculation zones introduced by the 110° expansion angle of the inlet cone. Because of these recirculation zones, the inertia of particles larger than about 5 µm aerodynamic diameter will cause their point-wise local concentration to differ from the concentration at the inlet entry. This concentration maldistribution continues to stage 1 primarily because of the annular collection plate at stage 0. The influence of the inlet cone aerodynamics on the performance of both stages means that the size of particles deposited on these plates will be uncertain unless the aerosol transport entering the impactor associated with calibration using monodisperse particles exactly simulates the in-use aerosol flow conditions. The degree of realism necessary in the calibration method has heretofore not been discussed in published calibrations of the ACI, introducing uncertainty in the size interpretation of the particle mass collected on stages 0 and 1 in practical applications of this impactor. Copyright

Verification of the EDA Concept Through an Assessment of Theoretical Failure Modes, Failure Mode Analysis, and Case Studies with Real Data

Previous chapters have presented the robust theoretical case for EDA in comparison with current ways of analyzing API mass distribution profiles from OIPs. This chapter is in two distinct parts; the first part examines from the theoretical standpoint, ways in which changes in APSD could potentially go undetected by EDA; the second presents a series of case studies with a variety of OIP types that demonstrate the appropriateness of EDA as a powerful, yet simple-to-use tool for in vitro assessment of CI data. Discussion of theoretical failure modes is presented for general awareness. In a given product/method development, each sponsor would have to conduct their own analysis of potential failure modes based on their situation. Similarly, the case studies are presented as illustrations of EDA and AIM applications for several real OIPs. Each sponsor may develop a different way to implement AIM and EDA, depending on their purpose.