The challenge of developing orally inhaled nasal drug products (OINDPs) is complicated by the interplay between drug-delivery devices and formulation. An article in the February 2013 issues of Pharmaceutical Technology and Pharmaceutical Technology Europe, “Improving Inhaled Product Testing: Methods for obtaining better in vitro-in vivo relationships,” discussed testing equipment and techniques. PharmTech recently interviewed the author, Mark Copley, sales director at Copley Scientific, to gain further insight into the importance of this topic.
PharmTech: What are some of the challenges in correlating device and formulation characteristics with clinical efficacy for OINDPs?
Copley: First, with OINDPs, successful drug delivery depends a great deal on the technique and health of the user. With a passive dry-powder inhaler (DPI), for example, an instruction to “inhale strongly and deeply” will result in the application of different amounts of energy for dose dispersion according to the strength and physiology of the user and any lung function impairment. Furthermore, the dispersive effect this produces depends on the characteristics of both the device and the formulation, complicating the ability to predict performance.
Second, there are challenges in establishing in-vitro tests that accurately represent the complex diffusion, sedimentation, and impaction mechanisms of deposition that occur in the throat and lungs. Cascade impaction, for example, is a very useful and widely applied technique, but the aerodynamic particle-size data it provides is indicative of likely in-vivo deposition behavior only; direct equivalence is not observed.
Finally, extending deposition behavior to draw conclusions about clinical efficacy is further complicated by factors such as the variability in clinical response that arises from loss of airway patency.
For all these reasons, securing robust in vitro–in vivo relationships (IVIVRs) for OINDPs is far more complex than for other pharmaceutical products such as tablets.
PharmTech: What factors are prompting current efforts to enhance inhaled product testing?
Copley: One driver for enhanced testing is the extension of OINDP technology to patient groups who may achieve lower delivery efficiencies than are indicated by the standard tests. This includes pediatric or older-age users, for example. Another is the use of OINDPs to deliver drugs that act systemically, for which it is particularly important to engineer robust delivery. More generally, enhanced testing supports the development of newer, more sophisticated OINDPs with more closely defined performance profiles.
For the generics sector, minimizing the extent of clinical trials is a challenging but valuable goal. Here, new guidance from the EMA points to the possibility of demonstrating bioequivalence through in-vitro testing alone. However, this depends on rigorously demonstrating the relevance and validity of the test methods applied and similarly places emphasis on ensuring that tests are as representative as possible.
PharmTech: If you had to highlight just one of the techniques for refining testing that you discuss which would it be and why?
Copley: It would have to be the application of breathing simulators combined with more representative upper airway (inlet) geometry, because of the interest that this is generating in the inhalation community, and because I think that this approach will substantially enhance our understanding of OINDP performance. The use of more representative breathing profiles is especially helpful for DPIs, which are complex to engineer. Here the use of breathing simulators enables researchers to fully scope the variability that may arise from patient capability and technique, supporting a quality-by-design approach and the successful implementation of OINDP technology for all user groups.
For more information, read Mark Copley’s article, “Improving Inhaled Product Testing: Methods for obtaining better in vitro-in vivo relationships.”