A mixing inlet is also required for the realistic APSD setup in order to decouple flow through the device from flow through the impactor. This is because cascade impactors are constant flow rate devices with calibrated performance at well-defined values (15 to 100 L/min for the NGI, for example). The mixing inlet allows for the use of patient-representative profiles while simultaneously maintaining flow through the impactor at the constant flow rate required for calibrated performance.
Measuring realistic APSD in this way effectively scopes the performance of the test (T) product relative to reference (R) over a broader range of more clinically representative conditions than is afforded by the compendial test setup. In this way, it can help to provide more robust evidence of BE for a specified patient population.
What other test methods and techniques are being used to improve the correlation between in vitro data and in vivo behavior?
The specification of dissolution testing in the PSG for the budesonide / formoterol fumarate / glycopyrrolate suspension MDI is noteworthy in this regard. There are currently no compendial methods for dissolution testing for OINDPs, and the community continues to debate best practice. However, there is no doubt that in vivo dissolution is a key step towards therapeutic efficacy with the potential to be rate-limiting for certain drugs. Where this is the case, dissolution testing is clearly a valuable addition to the in vitro testing roster for establishing BE, and there are commercial solutions already available for those looking to implement it.
The steadily expanding requirement to characterize the morphology of the emitted dose also reflects efforts to better understand the fate of the drug in vivo and ensure parity in this regard. While APSD measurements determine the amount of drug in relevant size fractions, morphological characterization of sampled particles can provide insight into, for example, agglomeration and particle shape, both of which may influence in vivo behavior.
Do you think that the guidance has broader implications with respect to the evolution of in vitro test methods?
It is likely that the new guidance will add impetus to current trends towards the adoption of more clinically representative in vitro test setups. Many are already using setups such as the one shown in Figure 1B to improve IVIVCs, thereby maximizing clinical relevance and the value of in vitro testing in product development. The PSGs add further incentive to adopt such strategies. While simple compendial methods offer the robust and reliable solutions needed for routine testing, notably in QC, realistic APSD setups and other tests that add in vivo insight can minimize and focus in vivo studies, making complementary application a highly productive and cost-efficient strategy.
