Issue link: https://www.e-digitaleditions.com/i/1524818
Inhalation August 2024 23 approved (or being developed) under an ANDA to a corresponding reference listed drug (RLD) product. e FDA has not yet provided clarity about how it will regulate the complex relation- ship between a generic MDI and its RLD, with regard to a propellant switch program. is paper proposes points to consider and possible pathways forward that relate to each of these con- cerns. Overall, advances in the design, manufacture and testing of MDIs have improved dramatically since the pre- and early propellant switch era of the 1990's [5-9]. is calls into question whether a regu- latory pathway that requires new NDAs or ANDAs is needed to adequately support safety, efficacy and quality for a propellant change in already approved MDI drug products. Rationale for requiring new NDAs in the 1990's for (current generation) HFA-based MDIs In 1956, the first approved CFC-based MDI appeared on the US market [10]. From a formula- tion and manufacturing perspective, CFCs were the ideal choice as MDI propellants. Several CFCs were available, which allowed great flexibility (e.g., as mix- tures) to obtain a wide range of working pressures, also allowing for ease in manufacturing (e.g., two- stage filling). CFCs are essentially inert (from the pharmaceutical perspective) and the inactive ingredi- ents used to formulate stable suspensions of an active pharmaceutical ingredient (API) in a canister were readily soluble in CFC propellants. In contrast, HFAs 134a and 227 (as well as HFA- 152a and HFO-1234ze(E) contain a distinguish- ing structural feature that is not present in CFCs: namely one or more carbon-hydrogen bonds. is seemingly minor structural difference contributes to large differences in physicochemical properties; par- ticularly for dipole moment and the resultant differ- ences in solubility behavior between CFC (1st gen) and HFA and HFO (2nd and 3rd gen) propellants (Table 1) [11]. is large difference in solubility behavior between CFC and HFA propellants meant that the inactive ingredients used as suspending agents in CFC-based MDIs could not be used in HFA-based MDIs. Find- ing inactive (aka, excipient) ingredients suitable for HFA-based MDI formulation that were also accept- able in terms of safety and tolerability proved elusive. Further, there is no corresponding HFA propellant for MDI use that is a liquid at ambient pressure and temperature. erefore, new manufacturing meth- ods and equipment had to be developed, tested and validated, in addition to developing new formula- tions with inactive ingredients having very different physicochemical properties. chronically ill patients with asthma and chronic obstructive pulmonary disease (COPD). Instead, it is reasonable to conclude that successful propellant switch scenarios may be achievable via the prior approval supplement (PAS) pathway for both NDAs and ANDAs that are currently approved. is appears feasible within the FDA's existing guidance and regulatory framework through the lens of science and progressive policy that can be aligned with the uniqueness of this situation. Introduction In the 1990's, for environmental protection reasons, chlorofluorocarbon (CFC) MDI propellants (aka "1st generation" propellants) were phased out and replaced with second generation hydrofluoroalkane (HFA) propellants, HFA-134a and HFA-227, which are now in current use [1]. All approved CFC-based MDI drug products were eventually removed from the market before or at government deadlines [2, 3]. Applicants were required to submit new, original NDAs including full clinical studies for each previ- ously approved, CFC-based MDI active ingredient using one of the 2nd generation propellants. ere were valid reasons for this approach at that time, which will be discussed more specifically in the next section of this paper. It is also important to note there were no generic MDIs on the US market during the propellant switch of the 1990's. Owing to their global warming potential, HFA-134a and HFA-227 [4] may soon be replaced with 3rd generation (aka "next gen") propellants HFA-152a and HFO-1234(ze)E, which have low global warm- ing potential (LGWP). It is anticipated that new MDI drug products will be developed using next gen propellants and that currently approved MDI drug products (under NDAs or ANDAs) will have to undertake a propellant/formulation switch pro- gram to maintain a sustainable position in asthma and COPD therapy. For additional perspective, both in the 1990's and today, the propellant switch programs were/are not related to the safety or efficacy of these products. Rather they were/are solely based on data-driven and scientifically sound environmental concerns in rela- tion to global warming. Of current interest are the following points: • By using modern approaches, the prior approval supplement (PAS) pathway may be the optimal reg- ulatory pathway today for approved MDI products under an NDA or ANDA to submit reformulated MDIs with next generation LGWP propellants. • e FDA has not yet made public the technical and clinical testing requirements (if any) for the above cases. • ere are unique statutory, regulatory and tech- nical relationships between an MDI currently