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Use of Realistic Testing for Lifecycle Changes: A Proposal for Discussion and Possible Future Regulatory Guidance

Sandell D.

Respiratory Drug Delivery 2020. Volume 1, 2020: 131-138.


Changes to a commercially available orally inhaled or nasal drug product (OINDP) are not uncommon. These are often due to a desire to introduce an improved product, such as adding a dose counter or a breath triggered version of a metered dose inhaler (MDI), or because of a new formulation ingredient like a new propellant. Rather than performing an in vivo study, companies typically try to justify the improved product by showing in vitro bioequivalence (IVBE) to the existing product. The key product performance characteristic used for these IVBE studies is the aerodynamic particle size distribution (APSD), typically determined under different experimental conditions using standard quality control test methods. The statistical evaluation is based on impactor sized mass (ISM) or fine particle dose (FPD), or some similar feature derived from the APSD such as the drug mass within a particular aerodynamic size band. In this paper I discuss different means to improve the relevance of the in vitro testing, aiming to provide data that can be trusted to imply in vivo equivalence more reliably. It is suggested that (1) the IVBE study is designed using similar principles to those used for in vivo studies; (2) APSD testing (to determine ISM, FPD or other in vivo predictors) is performed using a range of inhalation profiles (IPs) and anatomical mouth throat (MT) models to represent the intended patient population; and (3) acceptance criteria are based on the characteristics of the reference product.

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