Developing ways to evaluate in the laboratory how inhalation devices will be used by patients and care-givers: the need for clinically appropriate testing

Abstract

The design of methods in the pharmaceutical compendia for the laboratory-based evaluation of orally inhaled product (OIP) performance is intentionally aimed for simplicity and robustness in order to achieve the high degree of accuracy and precision required for the assurance of product quality in a regulated environment. Consequently, performance of the inhaler when used or even misused by the patient or care-giver has often not been assessed. Indeed, patient-use-based methodology has been developed in a somewhat piecemeal basis when a need has been perceived by the developing organization. There is, therefore, a lack of in-use test standardization across OIP platforms, and often important details have remained undisclosed beyond the sponsoring organization. The advent of international standards, such as ISO 20072:2009, that focus specifically on the OIP development process, together with the need to make these drug delivery devices more patient-friendly as an aid to improving compliance, is necessitating that clinically appropriate test procedures be standardized at the OIP class level. It is also important that their capabilities and limitations are well understood by stakeholders involved in the process. This article outlines how this process might take place, drawing on current examples in which significant advances in methodology have been achieved. Ideally, it is hoped that such procedures, once appropriately validated, might eventually become incorporated into the pharmacopeial literature as a resource for future inhaler developers, regulatory agencies, and clinicians seeking to understand how these devices will perform in use to augment ongoing product quality testing which is adequately served by existing methods.

Fig. 1

Idealized life cycle for a medical aerosol inhaler or add-on device such as a spacer or valved holding chamber. a The manufacturer bases the design of the new product upon input from perception of market needs augmented by clinician input. b Checks are in place to provide assurance that outputs at the various stages meet with patient needs, and the process continues post marketing of the production inhaler

Fig. 2

The Aerosol Drug Delivery Device (ADDD) design process envisaged in ISO 20072:2009; clinically appropriate test methods may be developed to evaluate specific test requirements related to the device functionality profile that has been assembled based on a risk assessment of those aspects of performance that are most vulnerable to failure in use

Fig. 3

”Delay” apparatus for use with pMDI-VHC combinations where it is necessary to simulate the effect of imperfect patient coordination on aerosol APSD and related sub-fractions of the emitted mass (CPM, FPM and EPM) in accordance with CAN/CSA/Z264.1-02 or draft USP chapter <1602>; The pMDI-VHC is shown attached to the apparatus just before the shutter drop to the ”open” position

Fig. 4

Nephele-Miller mixing inlet; the variable flow conveying the aerosol from the inhaler (pMDI illustrated, but could be used with a DPI or SMI) converges on axis with the constant flow of clean air supplied to the CI, exiting by a sharp-edged nozzle thereby avoiding turbulence and potential for losses of aerosol to interior surfaces of the inlet

Fig. 5

Complete sampling system used by Olsson et al. (78,79) for CI-based measurements of budesonide aerosols from a variety of OIP platforms in their demonstration of consistent IVIVC data [courtesy: Bo Olsson, Astra Zeneca, Sweden]

Fig. 6

Small, medium and large anatomically accurate adult oropharyngeal inlet models derived from data obtained by the oropharyngeal consortium (courtesy: Emmace Consulting AB, Sweden)

Fig. 7

Test facility for evaluating DPI emitted aerosol APSD developed by Chavan and Dalby (82,83); The DPI on test is contained within a small volume chamber with a computer-controlled proportionating valve at its entrance; operation of this valve controls the flow of air from the DPI Into the MLSI that measures emitted aerosol APSD (courtesy: Richard Dalby, University of Maryland)

Fig. 8

Electronic lung™ DPI testing apparatus developed at GSK plc, UK (84,85); the DPI is subjected to a patient-generated inhalation flow rate (Pressure Change (ΔP))-time profile using a breathing simulator comprising a computer-programmable bellows; the emitted aerosol passes via an anatomically accurate oropharyngeal cast to be collected in the sample chamber; after closing the valves to the chamber, a cascade impactor samples at a fixed flow rate (courtesy Geoff Daniels, GSK plc)

Fig. 9

Hydraulic Lung for generating ”human like” inhalation profiles for the evaluation of DPIs using the electronic™ lung DPI testing apparatus (86); the height of the water column can be related to the maximum inspiratory effort exerted by different patient groups potentially enabling the effect of obstructive disease as well as patient age to be mimicked in the laboratory (courtesy David Prime, GSK plc)