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Inhalation August 2024 25 may also offer a solution to the biological equivalence question, which is important in the regulatory context for a self-to-self comparison effort (i.e., before—vs. after—propellant change). In this context, self-to-self means comparing an already approved product to an updated product, by the same applicant, under the same NDA, which involves the propellant change. As an example of sophisticated contemporary think- ing in this regard, the FDA had expressed its will- ingness to consider both statistical and in vitro performance approaches to establish bioequivalence for certain generic drug products and routes of admin- istration (ROA), including aerosols [17]. Although this applies to generic drugs seeking initial approval, it is likely this approach can be extended and applied to a propellant switch program—to gather sufficient clinical information to support a propellant switch program for MDI drug products that were approved under an NDA or ANDA. If submitted under the same NDA or ANDA via a prior approval supplement, the quality requirements for approval of a propellant change for an approved MDI product may be as rigorous and data-based as would be required for a new NDA. Overall, the package of in vitro data may be derived from better- informed study designs and be more mechanistically understood than was possible in the 1990's. Such data provided on its own or coupled with relevant pharmacokinetic data (as self-to-self, pre- vs. post- change), and limited clinical data b [18] may offer a route forward for use of a prior approval supplement paradigm for currently approved MDI products— thereby balancing feasibility with low risk—in a pro- pellant change. It is therefore well worth exploring this possibility in more depth. Compare and contrast the current to next generation propellant switch: The criticality of regulatory pathways for NDAs and ANDAs NDA regulatory pathway recommendations Based on the sum total of technical and regulatory considerations discussed in this paper—in conjunc- tion with contemporary approaches to the design, development, characterization, manufacture and test- ing of MDIs—I propose that the prior approval sup- plement pathway under the same NDA (or ANDAs, see below) for approved MDIs updated with next generation propellants may be the optimal approach for gaining US regulatory approval. undertaken, let alone well understood. is remark is not meant to cast aspersions on the innovative and critical thinkers of that time. Rather, there simply was no medical, environmental or economic driver to deviate from a system that was working adequately in the pre- to early-1990's era. ere has been a considerable and steady iterative improvement in all aspects of MDI design, devel- opment, testing and manufacture since the mid- 1990's, when the first of the current generation of HFA-MDIs were marketed. Advances in computer technology, modeling and software development now make in silico approaches utilizing simulations and predictive modeling of critical performance attributes (e.g., APSD, DDU, etc. [5-8]) more fea- sible, useful and predictive in terms of the in vitro behavior of MDIs. Other important aspects include human factors testing to assess the effects of force to actuate, posture during use, cleaning, priming, rep- riming, handling and disposal on safety, efficacy or quality performance. e use of Quality by Design principles has also facil- itated the development of a well-defined design space, leading to a deeper and more mechanistic under- standing of what determines (and modulates) prod- uct quality [10]. is knowledge is then transferable and linked to appropriate requirements and controls for ingredient quality, manufacturing parameters and optimized testing regimens that better assure quality over shelf life. Such QbD concepts and approaches did not exist in the 1990's, whereas today, they are an integral part of rational drug product development. Improved technology and development approaches have therefore resulted in enhanced understanding of the factors that determine MDI performance in use, associated with greater predictability for critical performance attributes. ese outcomes have led to a corresponding increase in understanding and pre- dictability of the relationship between in vitro perfor- mance and in vivo response. It is well worth noting that any given in vivo response is often more variable and less precise to assess than corresponding in vitro measurements of the critical performance attributes leading to that response [15, 16]. e balancing trick has always been connecting the appropriate level of in vitro precision that is suf- ficient to meet in vivo goals for safety, efficacy and sustained product quality. Modern methods make attaining this goal a more realistic proposition. In terms of MDIs reformulated with new 3rd generation propellants, as part of a propellant change program, it seems reasonable that a pharmacokinetic approach b. In alignment with the FDA's Least Burdensome Provisions Guidance [18]: If the pre- to post-propellant change MDI meets all applicable specifications, plus any additional required comparative in vitro performance tests to support safety or efficacy, and either in vitro PK, or in vivo PK are comparable, then a requirement for additional clinical studies should be justified on a specific need for safety or efficacy that is not otherwise addressed by other data.