Development of realistic in vitro studies to assess robustness of dose counters/indicators in metered dose inhalers (U01)

Metered dose inhalers (MDIs) consist of a formulation, with active ingredient(s) and possibly excipients in a propellant contained in a pressurized canister, and are aerosolized using a valve fitted to an actuator. Dose counters/indicators are an add-on mechanism to MDIs and aid in tracking the number of doses remaining in the canister. According to the Guidance for Industry: Integration of Dose-Counting Mechanisms into MDI Drug Products (March 2003), in vitro testing (simulating both actual-use and misuse) and in-use studies are recommended to be conducted in order to establish functionality, reliability, and accuracy of dose counters/indicators in MDIs. The in-use studies supplement the in vitro testing and provide information regarding any problems when the dose counter/indicator is used in a clinical setting. The potential failure modes reported for MDI dose counters/indicators include, but are not limited to, undercounting, over counting and count(s) upon dropping.In general, in vitro robustness studies for MDIs include, but are not limited to, effect of dropping, shaking, exposure to temperature extremes, shipping, and storage under accelerated conditions on MDI drug product performance. Due to limited information available on the relevance of these in vitro robustness studies to clinical outcomes, it may be difficult to predict the failure modes of dose counters/indicators in MDIs under actual-use conditions. Therefore, there is a need to develop new or improve the existing in vitro studies used to assess robustness of dose counters/indicators in MDIs to better predict occurrence and type of failure for dose counters/indicators under actual-use conditions.The goal of this study is to develop clinically relevant in vitro studies to assess robustness of dose counters/indicators in MDIs representing the actual-use/misuse conditions. This study will consist of three phases. Phase 1: Select two commercially available MDIs with dose counters/indicators. Phase 2: Design new or modify existing in vitro methods and conduct in vitro robustness studies for the MDIs selected in Phase 1. Identify the intensity of in vitro tests needed to cause product failures, while ensuring that the proposed tests are predictive and relevant to actual-use conditions. Phase 3: Validate the proposed in vitro robustness studies using other marketed MDIs with dose counters/indicators.