2019’s product specific guidances for mometasone furoate, fluticasone propionate and others, included a reference to MDRS for the first time; however, the amount of drug PSD work required to be undertaken was undefined, and those guidances recommended the inclusion of appropriate data from ‘orthogonal’ methods that had yet to be defined or scoped out.
This meant an element of guess work was required from the sponsor, and usually several conversations with the regulators during and after IVBE data had been generated, to ascertain if the package of data submitted was sufficient in terms of the tests included, the number of batches analyzed and the testing protocol followed. The new guidances specifically recommend MDRS and clarify expectations for such testing.
Assuming that the data demonstrate statistical equivalence, these changes should provide sponsors with a much quicker route to submission and approval, with fewer questions around the makeup of the IVBE package submitted as long as the guidance has been followed. On the other hand, the agency now expects an increase in the amount of IVBE testing, and the newly recommended tests have their own challenges.
The recommendations for MDRS and dissolution testing are new — what are the benefits and challenges of those studies?
Both MDRS and dissolution testing require intricate method development and validation, and sample testing times are generally much longer than for standard nasal suspension testing techniques.
Drug PSD by a technique such as MDRS is a powerful tool, enabling the user to generate component specific particle size data in one non-destructive set of experiments on the same sample. Dissolution testing, using an appropriate method and sampling parameters, is also a valuable tool in comparing the dissolution characteristics of a reference and test product.
Applying both MDRS and dissolution tests in locally acting nasal spray formulations across reference and test products will allow the sponsor to confirm that the particle size of the delivered API, and its rate and extent of dissolution, are equivalent, supporting a claim of comparable dissolution and absorption characteristics, and consequently, equivalent clinical efficacy and safety.
The main challenge for MDRS work is in the length of time it can take to analyze one sample, often more than 8 hours, and sometimes much longer. Where there are at least 60 samples to analyze, and typical throughput is one sample per instrument, per day, a project may take several months to complete when method development, validation, statistical analysis and reporting are also factored in.
