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Development, Manufacture and Registration of Low GWP pMDIs in a Quality by Design Era

Britto L.

RDD Asia 2024. Volume 1, 2024: 90-102.

Abstract:

High global warming potential (GWP) propellants like HFC-134a and HFC-227ea, used in pressurized metered dose inhalers (pMDIs), significantly contribute to global warming. In response, several pMDI manufacturers are transitioning to low GWP propellants such as HFC-152a and HFO-1234ze(E). This shift is also driven by requirements from European Union (EU) F-gas regulations, US Environmental Protection Agency (EPA) hydrofluorocarbon (HFC) phase-down targets, National Health Service (NHS) Net Zero Carbon goals, and pharmaceutical companies’ carbon neutrality targets. European Medicines Agency (EMA) and the US Food and Drug Administration (FDA) have shared their current guidelines and perspectives to ensure safety, efficacy, and quality of these new pMDIs. Propellant replacement constitutes a major change to the finished product formulation and the potential to impact the inhaler device construction. Data addressing possible toxicity and local tolerance of the novel propellants together with data supporting maintenance of acceptable finished product performance needs to be provided. The latter include critical quality attributes (CQAs) of the finished product, namely delivered dose and aerodynamic particle size distribution (APSD). The goal of this article is to utilize scientific principles to facilitate this transition, while adhering to pharmaceutical quality standards. Utilizing 30 years of knowledge and experience gained during the transition of chlorofluorocarbons (CFC) to HFC pMDIs and applying Quality by Design (QbD) principles, the objectives are to optimize the development and manufacturing processes. This paper focuses on currently marketed pMDI products available globally (about 20 products). Additionally, it is assumed that no changes will be made to: (1) the active pharmaceutical ingredient (API); (2) label claim dose and (3) specifications of product CQAs.