ABSTRACT
An overview of the European Union (EU) regulatory process and guidance is made. Emphasis is placed on those topics that are most current, an issue, or where recent changes have or will be made. The status of two key guidance that provide the foundation to achieving: (a) pharmaceutical quality and (b) therapeutic equivalence for orally inhaled products (OIPs) are reviewed in further detail. It is noted that EMA has both key OIP guidance under parallel revision, based on experiences and feedback from stakeholders to re-assess issues such as dose proportionality, flow-rate dependency, stage grouping, requirements on data for an inhalation spray together with a spacer/holding chamber, the possibility of using new abbreviated methods, to conduct intra- and inter-device variability for delivered dose uniformity in one test, guidance on how to justify that the manufacturing process may be considered as a standard process, evaluating essential requirements for CE marked and non-CE marked devices, and updating of relevant parts to reflect the concepts of ICH Q8/Q9/Q10 and life cycle management. Industry views on the EU regulatory process are considered in how they could be used to enhance the future direction of guidance. A significant change to the EU regulatory scene will occur as the United Kingdom (UK) is leaving the EU. What UK national regulatory process will be created remains to be seen, but there will be consequences for industry when seeking marketing authorisations whether for within the EU or the UK. The UK leaves the EU in March 2019, thus little time remains in which all stakeholders have to respond to this significant event to achieve a seamless regulatory process transition. Underpinning the quality requirements are the EU Pharmacopoeial standards and methodologies. European Pharmacopeia OIP monographs are discussed and the current work program of the Inhalanda working party is briefly reviewed. The British Pharmacopeia will also have a new role once the UK has left the EU, and its activities and relationship to the European Pharmacopeia is discussed. The device part of an OIP is critical, as signified by new medical device regulations (MDR 2017/745) within Europe coming into force in 2020. The areas where significant changes occur compared to the previous regulations are highlighted, and the implications of these are considered. Finally, we focus on the in vitro bioequivalence requirements and considerations for generic OIPs. Generic OIPs provide many challenges not faced by other dosage forms. Some of the difficulties encountered that prevent approval being gained are illustrated with possible mitigation actions. Aspects of dose linearity are considered and when a biowaiver may be applicable.
