Issue link: https://www.e-digitaleditions.com/i/1524818
Inhalation August 2024 29 also change its propellant, provided that ANDA matches the same propellant switch requirements as its corresponding RLD. Requiring new NDAs for all currently approved MDIs would be more likely to lead to drug short- ages and loss of therapeutic options, and jeopardize the MDI generic program for years to come; with- out adding substantive value or risk reduction to chronically ill patients. Regardless of how the FDA regulates the propel- lant switch program, a holistic consideration of both RLD and generic MDI drug products merit a coor- dinated process to ensure that public health needs are met and that the full armamentarium of MDI drug products remains available to the public. References 1. Montreal Protocol on Substances that Deplete the Ozone Layer (with annex). Concluded at Montreal on September 16, 1987. https://treaties.un.org/doc/ publication/unts/volume%201522/volume-1522-i- 26369-english.pdf. 2. Use of Ozone-Depleting Substances; Removal of Essential-Use Designations. https://www.feder alregister.gov/documents/2005/04/04/05-6599/use- of-ozone-depleting-substances-removal-of-essential- use- designations. 3. Phase-Out of CFC Metered-Dose Inhalers Con- taining Flunisolide, Triamcinolone, Metaprotere- nol, Pirbuterol, Albuterol and Ipratropium in Combination, Cromolyn, and Nedocromil - Ques- tions and Answers. https://www.fda.gov/drugs/ information-drug-class/phase-out-cfc-metered- dose-inhalers-containing-flunisolide-triamcinolone- metaproterenol-pirbuterol-0. 4. Transitioning to low-GWP Alternatives in Aerosols. https://www.epa.gov/sites/default/files/2016-12/ documents/transitioning_to_low-gwp_alternatives_ in_aerosols.pdf. 5. Effects of Realistic In Vitro Test Factors on the Aerosol Properties of Metered-Dose Inhalers (2022). https://www.fda.gov/drugs/regulatory-science- action/effects-realistic-in-vitro-test-factors-aerosol- properties-metered-dose-inhalers. 6. Taiaat M, Si X, Xi J. Effect of MDI Actuation Tim- ing on Inhalation Dosimetry in a Human Respira- tory Tract Model. Pharmaceuticals, 2022; 15(1):61. 7. Borghardt J, Weber B, Staab A, Kloft C. Pharma- cometric Models for Characterizing the Pharmaco- kinetics of Orally Inhaled Drugs. AAPS J, 2015 Jul; 17(4):853-870. 8. Sheth P, Stein S, Myrdal P. Factors Influenc- ing Aerodynamic Particle Size Distribution of Sus- pension Pressurized Metered Dose Inhalers. AAPS PharmSciTech, 2015 Feb; 16(1):192-201. lant choice. So the door to propellant flexibility for ANDAs (compared to their corresponding RLDs) may be open and worth exploring; unless the FDA chooses to close it. Comments regarding gray practices In this paper, I have defined gray practices as those that exploit the regulatory framework with the intent to obstruct, delay or otherwise inhibit the emergence of generic, 505(b)(2) or other new drugs. As an example, the United States Federal Trade Com- mission (FTC) recently issued warning letters to a number of medical device and drug manufacturers, disputing more than 100 patents for being "improp- erly listed in the FDA's Orange Book" [28]. is FTC action includes some MDI drug products. As the propellant switch program emerges into existence for MDIs, it behooves all parties, as well as author- ities with a mandate for maintaining public health, to avoid this problem, lest a set of technical/legal issues be magnified into a national crisis based on the unavailability of essential inhaled medications. In this context, it is reasonable to propose that both the FTC and FDA continue to watch the propellant switch space for this type of improper product pro- tection, as well as other gray practices unspecified here, and act accordingly. Summary and conclusions e current switch scenario for approved MDIs to reformulate with next generation propellants (i.e., HFA-152a and HFO1234ze(E) bears some simi- larities to and many notable differences from the CFC to HFA switch of the 1990's. As these new propellants are more alike in properties to the cur- rently used propellants (HFA-134a and HFA-227), the switch to next generation propellants is much less dramatic in physicochemical nature than the previous 1990's scenario. Advances in MDI design, development, characteriza- tion, manufacture and testing—coupled with more predictive models, relevant in silico simulations and QbD approaches—provide for more powerful con- nections between in vitro performance and predicted in vivo performance. is scenario strongly suggests that something less than full clinical studies and new drug applications should be necessary to assure safety and efficacy as a result of a propellant switch for already approved MDIs. It appears that all the necessary in vitro and rele- vant in vivo data (to show self-to-self equivalence, e.g., pharmacokinetic similarity) can be submitted via the PAS regulatory pathway. ese data may support safety and efficacy at relatively low risk to both producer and patient communities. is pathway would also preserve the NDA number and would further allow any corresponding ANDA to