Many factors, including the test environment, can cause variabilityin OIP testing, compromising the demonstration of therapeutic equivalence. Sources of variability are typically discussed within the context of cascade impactor measurements, but some sources apply equally to all types of testing. For MDIs specifically, examples include shaking (speed, angle, and duration), priming (and time delay between firing), actuation profile, and electrostatics.
Automated shake, fire and flow control platforms provide closely controlled, rigorously repeatable conditions for actuating MDIs both for analysis and to waste. Using such systems has been shown to reduce the variability of MDI test data relative to manual practice, a critical gain. These types of systems also support rigorous investigation of the impact of factors such as time delay between shaking and firing to assess the in-use potential for settling or creaming in reformulated products. Furthermore, the flexible configurations possible with the leading automated systems allow analysts to rapidly and efficiently step through a battery of tests relevant to the demonstration of therapeutic equivalence.
Which brings us to the last issue, productivity. Current reformulation efforts call for extensive testing with many facing aggressive timescales. Automation can give a much-needed boost to productivity, with studies indicating a reduction in the time required for delivered dose testing and APSD measurement on the order of 30% via the adoption of automated shake, fire, and flow control alone.
Keeping your automation toolkit up to date and releasing analysts from repetitive tasks (as far as possible) is worthwhile, with automation of drug recovery tasks likely to offer a good return on investment. Even simple devices such as those that automate the dissolution and recovery of drug from a dose uniformity sampling apparatus can make a difference but there are also more sophisticated solutions available that handle everything from solvent dispersion to solution presentation, for cascade impaction measurements.
More generally it pays to be aware that some of the test set-ups required are relatively complex with the EMA guidance pointing, for example, to the need to test LGWP MDIs with spacers and holding chambers. Associated compendial requirements, as detailed in USP <1602> necessitate the use of a breathing simulator for this task, to mimic the patient’s inhalation profile, and, in some instances, facemasks, which can be difficult to interface securely with test apparatus. Investing in solutions that are less prone to manual error can pay dividends when analytical teams are under pressure.
Any last words of advice on reformulation activities and the role of in vitro testing in the LGWP transition?
History and market economics suggest that the transition to low GWP propellants will gain pace. Forerunners are heavily invested and closing in on the delivery of new products; those companies who have delayed the switch face an unpredictable market going forward, with respect to both propellant price and MDI demand.
Focusing on in vitro testing, the new EMA guidance confirms the potential for the right equipment and methods to support LGWP MDI applications right through to market authorization; and if not, then to reduce the evidence required from PK and PD studies. In vitro tests are prized for their repeatability, ease of validation, speed and low cost. Leveraging them to maximum effect is critical in the race to retain necessary inhaled drug products, while reducing their environmental impact.
