Which in vitro tests are specified for the demonstration of therapeutic equivalence for MDIs reformulated with LGWP propellants?
The new Q&A references existing EMA guidance on well-established in vitro test methods for the demonstration of therapeutic equivalencebetween inhaled products which includes test requirements relating to the active drug substance, product performance and patient experience. For example, there is a need to demonstrate that the product contains the same active ingredient, in the same solid state, and that delivery devices handle in a similar way and present comparable resistance to air flow (to within +/-15%).
In practice, in vitro methods including delivered dose uniformity testing, cascade impaction, plume geometry and spray dynamics, as well as complementary issue-specific methods, such as those used to measure the force and temperature associated with dose delivery, are used to address the requirement that:
“Any qualitative and/or quantitative differences in excipients should not influence the performance of the product (e.g. delivered dose uniformity, etc.), aerosol particle behaviour (e.g. hygroscopic effect, plume dynamic and geometry and/or be likely to affect the inhalation behaviour of the patient (e.g. particle size distribution affecting mouth/throat fee or “cold Freon effect).”
The cold Freon effect is the inadvertent reaction to the chilling sensation at the back of the throat associated with propellant evaporation and presents a prime example of how switching to a propellant with different properties can impact patient experience and indeed product usability, a highlighted concern of the regulators.
The key point to recognize is that there are established tests to cover all the informational requirements, including options such as the use of more clinically realistic throat models or investigating the impact of actuation parameters to further demonstrate robust therapeutic equivalence.
What solutions and strategies would you recommend for optimizing the cost-efficiency and productivity of in vitro testing required for the transition?
If you are aiming for market authorization via the in vitro only route, or even just looking to maximize the weight of evidence from in vitro assessments, then it pays to be smart about your testing schedule and practice. Optimizing test set-up; reducing variability; and maximizing productivity are essential for avoiding delays and unnecessary expense. Given the criticality of performing in vitro tests as uniformly, consistently and accurately as possible, automation should definitely be a high priority.
The pharmacopoeias are an excellent place to start when it comes to test set-up for in vitro methods; however, we can also look beyond the pharmacopoeias for potentially useful strategies. One particularly useful set-up involves the use of more anatomically relevant throat geometries (like the Alberta Idealised Throat) to interface the inhaler and test apparatus. The standard USP/Ph. Eur. induction port has a basic standardized geometry that is known to capture less of the dose than would typically deposit in a patient’s throat. Using a more realistic geometry can offer a more clinically-relevant assessment of both reference and reformulated product and provide more compelling evidence of equivalence.
