Table III.

Comparison of the Recommendations for Drug Substance, Formulation, and Device of Orally Inhaled Product Equivalence

Active pharmaceutical ingredients (API)	Similarities: contain the same active substance Differences: EMA, TGA: • Same form of active substance (i.e., same salt, ester, hydrate or solvate, etc.) • For the active substance in the solid state (powder, suspension): any differences in crystalline structure and/or polymorphic form should not influence the dissolution characteristics, the performance of the product, or the aerosol particle behavior FDA—nebulized budesonide inhalation suspension • Sameness of polymorphic form of the drug substance • Sameness of shape (crystalline habit) of the drug substance FDA—albuterol sulfate MDI and FP-SX DPI: not mentioned
Inactive ingredients	HC: qualitatively (Q1) the same and quantitatively (Q2) essentially the same (within ±10% difference)
	EMA, TGA:
	• For nebulization solution with the same qualitative and quantitative composition as the reference products, the clinical study may be waived
	• Any qualitative and/or quantitative differences in excipients should not influence the performance of the product, aerosol particle behavior and/or be likely to affect the inhalation behavior of the patient
	• Any qualitative and/or quantitative differences in excipients should not change the safety profile of the product
	• In case of new propellants and excipients, more studies are recommended: clinical efficacy, safety profile, toxicology, local tolerability
	FDA:
	• Albuterol MDI and nebulized budesonide inhalation suspension: Q1 the same /Q2 essentially the same (within ±5% difference from RLD)
	• FP-SX DPI: If Q2 different from RLD, the sponsor should justify and provide pharmaceutical development data, involving in vitro testing of multiple drug-to-excipient ratios that encompass combinations below and above the ratios used in the T and R products
Device	HC: recommends qualitative and quantitative analysis of
	• The physical attributes (e.g., dimensions, materials used)
	• Operating characteristics of the delivery devices - functionality of the system
	EMA, TGA:
	• Similar inhaled volume through the device (within ±15% difference)
	• Similar handling of the inhalation devices for the test and the reference products
	• Similar resistance to airflow (within ±15% difference)
	FDA:
	A sponsor is encouraged to submit a working model and engineering drawings of the product to the Office of Generic Drugs (OGD) prior to ANDA submission
	• For FP-SX DPI, the device of the test product should have the following characteristics: passive, pre-metered multi-dose format, with 60 doses, external operating procedures consisting of 4 steps as per RLD labeling, similar size and shape to the RLD product device, comparable device resistance to the RLD product and with dose counter.
	• For albuterol MDI, the device should be similar in shape and size to the RLD product device. The test product should have a dose counter if the RLD product has one
Physicochemical properties of drug product	HC: Physicochemical properties are recommended
	• For aqueous product: description, osmolality (or osmolarity), surface tension, viscosity, pH, buffering capacity and specific gravity
	• MDI: surface tension, viscosity, specific gravity, vapor pressure, freezing point, and refractive index
	• DPI: particle size distribution of the carrier (if present), bulk and tapped density, particle morphology (shape, texture, and surface properties), melting point, electrostatic charge, porosity, specific surface area, hygroscopicity, and moisture content
	Acceptance criteria: they are should be essentially the same, within ±10% difference
	Other jurisdictions do not have these criteria

EMA European Medicines Association, TGA Therapeutic Goods Administration, FDA Food and Drug Administration, DPI dry powder inhaler, MDI metered-dose inhaler, RLD reference listed drug