EMA Guidance: Requirements for Demonstrating Therapeutic equivalence between Orally Inhaled Products (OIP) and Chronic Obstructive Pulmonary Disease (COPD)
- Sharan Murugan
- Jul 23
- 2 min read
On 14 July 2025, the European Medicines Agency (EMA) published the final revised guideline titled "Guideline on the requirements for demonstrating therapeutic equivalence between orally inhaled products (OIP) for asthma and chronic obstructive pulmonary disease (COPD)".
This update (Revision 2) modernises and clarifies the requirements for companies developing generic or hybrid inhaled products that claim therapeutic equivalence (TE) to reference medicines — covering both single active substance products and fixed combination inhalers.
Stepwise Approach: In Vitro, Pharmacokinetics, and Beyond
The new EMA guideline keeps the stepwise approach at its core:
✅ First, applicants must perform an in vitro comparison, including:
Aerodynamic Particle Size Distribution (APSD)
Delivered dose
Device resistance
Qualitative and quantitative excipient differences
If all predefined in vitro criteria are fulfilled, TE can be established without human PK studies.
✅ If in vitro criteria are partly unmet, the guideline prefers demonstrating TE through pharmacokinetic (PK) studies:
PK studies can act as surrogates for efficacy (lung deposition) and safety (systemic exposure).
These are typically single-dose, cross-over studies in healthy volunteers.
Activated charcoal may be used to block GI absorption when needed.
The guideline (finalised on 14 July 2025, effective 1 February 2026) introduces or clarifies:
Spacers:Â TE must be demonstrated with and without named spacers if used.
Nebulisers:Â Products for nebulisation must demonstrate TE with at least one named nebuliser.
Suprabioavailability:Â If lung deposition is too high, lower strength reformulation and re-validation are needed.
Flow dependency:Â Especially for DPIs, flow rate dependency must be checked across patient groups.
Fixed combinations:Â Each active substance must independently meet TE criteria.
Pharmacokinetics (PK) studies must:
Compare systemic exposure (AUC and Cmax) for safety.
Demonstrate lung deposition equivalence (using AUC(0–t) and/or early partial AUC).
✅ For substances with negligible GI contribution, PK studies may be conducted without charcoal.
✅ For significant GI contribution, use charcoal or partial AUC approaches.
Acceptance criteria:
90% CI of test/reference ratio within 80–125%.
Systemic exposure from test product must not be higher than reference.
PK is generally preferred. However, in exceptional cases (e.g., β2-agonists) where PK data isn’t sufficient, applicants can propose PD or clinical endpoint studies.
When devices form an integral part of the medicinal product, applicants must conduct usability studies:
At least 15 participants per user group (e.g., asthma, COPD, caregivers).
Test product-naïve and experienced users.
Study should simulate real-life use: opening, actuating, dosing.
For more details, read the full guideline here: