Generic inhalers and the problem of copying a device

Three metered-dose inhalers sit in Part II of FDA's June 2026 list of off-patent drugs with no approved generic¹: one albuterol inhaler, one levalbuterol inhaler and one fluticasone and salmeterol inhaler. All three have no patents or exclusivity left to block a copy. FDA put them in the section reserved for products where generic development "may raise potential legal, regulatory, or scientific issues."

Inhalers turn up there because a generic inhaler is three things at once: a drug, a formulation that has to form particles small enough to reach the lungs, and a device that a patient has to use correctly. FDA's GDUFA III commitment letter² names metered-dose inhalers twice in its definition of complex products, once as a complex dosage form and once as a complex drug-device combination.

This piece explains how FDA decides that a generic inhaler matches the brand, how it compares the devices, and where the agency's research is pushing next. GxRadar's companion explainer on complex generics covers the wider category.

Why the tablet test is not enough

For a typical tablet, FDA judges a generic by comparing blood levels of the drug in healthy volunteers, the test explained in GxRadar's piece on the 80-125 rule. Most inhaled drugs act in the lungs, and the amount that shows up in the blood is an indirect signal of how much reached the airways and where.

Two FDA scientists laid out the problem in a 2020 review in Pharmaceutical Medicine³. An inhaled product's performance, they wrote, "is impacted by numerous factors derived from the product's formulation, delivery to a local site of action within the lung, the performance of the device, and the patient population that uses the medication." The approval and use of generics in this class "has lagged behind" as a result.

The Orange Book reflects the same caution. Its preface⁴ says FDA "does not consider different metered aerosol dosage forms containing the same active ingredient(s) in equal strengths to be therapeutically equivalent unless the drug products meet an appropriate bioequivalence standard." Those that do get the AB rating explained in GxRadar's guide to therapeutic equivalence codes.

The weight-of-evidence approach

FDA's answer is what it calls an aggregate weight-of-evidence approach. Instead of one decisive study, a generic inhaler has to pass several, and the evidence is judged together. The same review describes it as a paradigm "where studies and conditions, when taken together, establish equivalence in device performance, systemic exposure, and local drug delivery."

That last item is the expensive one. Comparative clinical endpoint studies enroll patients and compare a clinical outcome, and they are the step FDA has worked hardest to replace. In its FY 2025 GDUFA Science and Research Report⁵, FDA says its research is "the reason that most PSGs on OINDPs now include recommendation for an option to demonstrate bioequivalence (BE) that is more efficient than conducting a comparative clinical endpoint (CCEP) BE study." One project cited there used particle-morphology imaging on dry-powder inhalers to support an approach "in lieu of conducting a CCEP BE study" for generics formulated the same as the reference.

Each inhaler's exact study package is set out in its product-specific guidance⁶, the documents GxRadar describes in its PSG explainer. FDA published five new and nine revised inhalation and nasal guidances in fiscal 2025, all of which it says were "directly impacted by GDUFA-funded research."

How FDA compares the device

A generic inhaler does not have to look identical to the brand, but differences in how it is used have to be justified. FDA set out its method in a January 2017 draft guidance, Comparative Analyses and Related Comparative Use Human Factors Studies for a Drug-Device Combination Product Submitted in an ANDA⁷, announced in the Federal Register on Jan. 17, 2017⁹. It covers all generic drug-device combinations, from inhalers to auto-injectors, and it is still a draft.

FDA's test is substitution. According to the guidance text⁸, FDA "intends to consider whether the generic combination product can be substituted for the RLD without the intervention of a health care provider and/or without additional training prior to use." Developers are told to "generally seek approval of a presentation approved for the RLD" and to minimize differences.

It recommends three threshold analyses:

• Labeling comparison: a side-by-side, line-by-line comparison of the prescribing information, instructions for use and device descriptions.
• Comparative task analysis: breaking down each step a user takes with each product to find where errors could differ.
• Physical comparison: obtaining the brand and examining it by sight and touch against the proposed device.

The results sort a product into one of three outcomes. With no design differences, extra human-factors data are "likely" unnecessary. A minor difference, one that does not affect an "external critical design attribute," is likely acceptable if the analyses show it really is minor. An "other" difference that may affect how the product is administered leads FDA to suggest redesigning the device, or to request a comparative use human factors study. In that study, representative users simulate use of both products, and the generic's use error rate for the affected task must be shown to be no worse than the brand's.

Inside FDA, MAPP 5223.6¹⁰, effective June 7, 2022, describes how the Office of Generic Drugs and the Office of Surveillance and Epidemiology assess these user-interface comparisons.

Where the research is heading

FDA's fiscal 2027 research priorities¹¹ name inhalers in two of eight areas. One calls for better dissolution and modeling tools for inhalation products used alongside pharmacokinetic studies. Another seeks alternatives to comparative use human factors studies, and "economically feasible approaches" to help generic products move to "more environmentally friendly propellants and device components." In fiscal 2025, FDA-funded work also validated a questionnaire capturing patients' perceived effort and comfort with dry-powder inhalers, which the report says gives developers "an alternative method to assess DPI usability."

FDA and the grant-funded Center for Research on Complex Generics held a two-day workshop on inhalation bioequivalence on Oct. 14 and 15, 2026¹². Its description says recommendations for these products have moved "toward option-based bioequivalence frameworks," with lab, human and computer-model methods as "viable alternatives to comparative clinical endpoint studies."

Quality problems do surface after approval. GxRadar's count of openFDA enforcement records¹³ from June 2012 through Oct. 28, 2026 finds 62 recall records for oral inhalation products, brand and generic combined: 3 Class I, 45 Class II and 14 Class III. The full series is on GxRadar's recalls page, and the 2023 supply squeeze on albuterol is covered in a separate article.

Anyone handed a generic inhaler that looks or works differently from the last one can ask the pharmacist to show how it is used. The 2017 device guidance remains in draft, and the three Part II inhalers will show up again, or move, when FDA publishes its next off-patent list in December 2026.