EMA issues guidelines on quality, therapeutic equivalence of inhaled drugs

The European Medicines Agency (EMA) has released a guideline on assessing the quality of inhaled and nasal medicines, as well as a guideline on demonstrating therapeutic equivalence (TE) of orally inhaled products (OIP) for asthma and chronic obstructive pulmonary disorder. Both guidelines will take effect on February 1.

These two guidelines are complementary and should be read together for a complete understanding. These versions replace the two draft guidelines that were issued in February 2024. (RELATED: Euro Roundup: EMA seeks feedback on quality, therapeutic equivalence of inhaled drugs, Regulatory Focus 18 April 2024)

Pharmaceutical quality

EMA stated the guideline on pharmaceutical quality consolidates information from earlier documents and has been updated to reflect recent advancements in the field.

The guideline covers pressurized and non-pressurized metered-dose inhalers (MDI), dry powder inhalers (DPI), nebulizers, and pressurized metered-dose nasal sprays, nasal powders, and nasal liquids. Liquid inhalation anesthetics and nasal ointments, creams, and gels are excluded from its scope.

The guideline directs sponsors of inhalation products to describe the active substance, the composition of the finished product, conduct pharmaceutical development studies, and describe the control of excipients. Similar information should also be submitted for nasal products.

“For all inhalation finished medicinal products containing an active substance that is not dissolved at any time during the finished product manufacture, storage or use, the particle size of that active substance is a critical parameter. A complete description of the particle-size adjustment process (e.g., jet-milling or spray-drying as micronisation process) and the in-process controls should be provided. Sufficient details need to be included in the active substance section (S) and referenced in pharmaceutical development section (P.2), to assure the required quality of the micronised active substance,” EMA wrote.

The guideline adds that manufacturers should provide a detailed description of the manufacturing process for the finished medicinal product, including filling and packaging.

Therapeutic equivalence

The guideline second guideline addresses how to demonstrate TE between OIPs containing the same active moiety as the reference product.

EMA said the final version clarifies that the “demonstration of TE between OIP is based on a stepwise approach, where TE could be demonstrated in vitro if all in vitro requirements are fulfilled or else preferably by means of pharmacokinetics if equivalent systemic exposure (as a surrogate marker for safety) and equivalent lung absorption/deposition (as a surrogate marker for efficacy) is demonstrated in spite of some in vitro differences.”

The guidelines recommend against using pharmacodynamic or clinical endpoints to demonstrate TE, as these are considered insensitive.

The guideline addresses general considerations for investigating therapeutic equivalence, the in vitro criteria for assessing TE, the use of pharmacokinetic (PK) studies to investigate equivalence regarding safety, and the PK studies to evaluate efficacy.

The guideline states that “the test and reference products should be comparable to conclude on TE. The in vitro comparability exercise should be performed and evaluated based on a study protocol including methods of comparison and acceptance criteria. TE is sufficiently demonstrated if the test product fulfils all the following in vitro criteria as compared to the reference product: The test product contains the same active substance as the reference product (i.e., same salt, ester, hydrate or solvate).”

EMA guideline on quality of inhalation products; EMA guideline on COPD

EMA issues guidelines on quality, therapeutic equivalence of inhaled drugs

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