Issue link: https://www.e-digitaleditions.com/i/1524818
28 August 2024 Inhalation lants. It is worth pointing out that while MDIs are justifiably seen as "complex generics" for those prod- ucts that are licensed, they have already overcome the hurdles associated with the identified complexities to achieve their existing approval as generic MDIs. By virtue of this, the ANDA manufacturer has demon- strated that it has sufficient product knowledge and understanding for its MDI to be listed in the FDA's Orange Book as equivalent. It follows that the ANDA applicant should understand the performance of its MDI drug product as well as the RLD applicant. As an example, the product specific guidance (PSG) for albuterol MDI (2023) contains comprehensive bioequivalence recommendations for gaining ANDA approval [26]. However, this is for initial approval and has no direct bearing on a propellant switch program for any approved ANDA that followed this guidance. From an approved ANDA perspective, the propellant switch scenario is no more (and no less) complex for an approved ANDA than it is for an approved NDA. In other words, what is required for an NDA propellant switch as a PAS should equally apply to the corresponding approved ANDA(s). Supply chain considerations ere are currently only two next generation of LGWP propellant candidates. It remains to be seen how patents, supplier-customer agreements and any potential per-and polyfluoroalkyl substance (PFAS) restrictions may impact propellant availabil- ity. Other factors that may impact propellant avail- ability include terrorism, geopolitical conflicts and cybersecurity issues. Overall, supply chain vulnera- bility is arguably the same or worse now than it was in the 1990's [27]. To that end, if an ANDA were allowed to use a differ- ent next generation propellant (or mixture of them) from its RLD, this may allow for greater flexibility and supply chain robustness (through diverse pro- pellant options). In a switch program, that approach could theoretically extend to include all MDIs (NDA- and ANDA-based). Is there regulatory room to proactively maneu- ver around some of these vulnerabilities by having greater freedom of propellant choice? To address this, let's consider the aforementioned albuterol PSG in terms of the propellant. e FDA recommends that the ANDA MDI formulation be qualitatively (Q1) and quantitatively (Q2) the same as the RLD MDI. However, even for initial approval, this is a recom- mendation only; there is no statutory or regulatory Q1/Q2 mandate for MDIs in terms of propel- testing processes should support a situation where full CMC/Quality data and limited clinical data (if needed) may be submitted via the prior approval supplement pathway. is approach could apply to NDAs as well as ANDAs. In a PAS approach paradigm for ANDAs and NDAs, there is the opportunity for approved MDIs to be treated comparably (i.e., treating similar situations alike is an integral part of the FDA's regulatory pro- cesses [24]) c . e underlying rationale for such com- parability in regulation is based on the premise that the propellant transition scenario is a self-to-self comparison in either the NDA or ANDA case (cur- rent propellant to new propellant). In other words, whatever the NDA applicant has had to do in its PAS program for its MDIs, the ANDA applicant must do for their own generic products. ere are narrow restrictions for approved ANDA products to submit new clinical data relative to that which an RLD may have done (i.e., no new indica- tions claimed, etc.). If supportive clinical data are lim- ited to a bioavailability study or a pharmacokinetic data comparison (i.e., self-to-self but not test-to-ref- erence) as part of a post-approval propellant switch program for an approved NDA or ANDA MDI, then it appears that the wording in 21CFR 314.54(a) below does seem not to prohibit such an approach being submissible as a post-approval change [25]. Sec. 314.54 Procedure for submission of a 505(b)(2) application requiring investigations for approval of a new indication for, or other change from, a listed drug. e Federal Food, Drug, and Cosmetic Act does not permit approval of an ANDA for a new indication, nor does it permit approval of other changes in a listed drug if investigations, other than bioavailability or bioequivalence studies, are essential to the approval of the change. Any person seeking approval of a drug product that represents a modification of a listed drug (e.g., a new indication or new dosage form) and for which investigations, other than bioavailabil- ity or bioequivalence studies, are essential to the approval of the changes may, except as provided in paragraph (b) of this section, submit a 505(b) (2) application. is 505(b)(2) application need contain only that information needed to support the modification(s) of the listed drug. Complex generic MDIs post-approval It remains to be seen how the FDA will handle generic MDI post-approval reformulation with new propel- c. "In Bracco, the issue was that the FDA had chosen to regulate most ultrasound contrast agents as drugs, but one as a medical device. e court, following a long line of court decisions, held that similarly situated parties (and products) must be treated in a similar fashion, and appropriately left it to the FDA to decide whether the products would be regulated as drugs or devices. e FDA chose uniform drug regulation, which has lasted since that time." [24].