Nasal spray products have been traditionally recognized as complex products, physically constituted out of a formulation system, either in form of a suspension, emulsion or a solution, and a delivery device, composed out of multiple components. Challenging development process is even harder in absence of clear and aligned quality requirements and expectations from wordlwide health regulatory bodies. This doctoral thesis presents a comprehensive approach of development of nasal spray product in a form of a suspension. First important aspect is understanding of formulation and delivery device properties, which have potential to impact quality of the product. Quality can be monitored with in vitro analytical methods. In vitro testing can be done for purposes of decisioning process during development of the product, or can be used as confirmation of suitable and targeted performance in in vitro bioequivalence studies. First chapter is devoted to Design of Experiment approach with aim of studying both formulation and delivery device properties, which have impact on quality of the product. Experimental design included combinations of three factors, viscosity of suspension, nozzle orifice diameter and shot weight. Followed responses were droplet size distribution and spray pattern obtained by in vitro tests. In addition, the amount of work needed for specific product actuation was integrated from force–displacement profiles and used as response. Results were fit to quadratic model by regression, which additionally allowed determination of second-order and interaction effects between factors. Optimized models were used to create response surfaces. Practical application of response surfaces was demonstrated by definition of optimal levels of factors based on desired performance, i.e. demonstrating a route for rational selection of specification limits of such pharmaceutical product. In vitro analytical methods used to evaluate nasal spray products are associated with a high degree of variation, and should be developed in a way that the observed total variation of results is in major part representative for product performance. Furthermore, methods should be robust to minimize contribution of random factors to the results variation. Development of spray pattern test, presented in the second chapter, is one of the most challenging. First step of the development was definition of a robust product-shaking procedure in accordance with instruction to patient. In vivo relevant actuation parameters were determined based on the comparison of the droplet size distribution results of manual actuations performed by three volunteers with those obtained by automated actuation profiles. Other method parameters related to visualisation part were determined. The final in vitro method was tested to evaluate the contribution of individual factors and interactions to the observed variance of results by using gauge repeatability and reproducibility model. It was found that the time lag between consecutive actuations significantly influences the variability of SP area, suggesting the importance of determining a recovery period. Factors time point and day were found to have the potential to impact results. Significant differences were observed when the same product was tested in different laboratories. By using this statistical approach key random factors were identified and appropriate control strategy over these factors was set to assure that assessed total results variation is representative for product performance. The same general approach is not only applicable to the development of in vitro methods for nasal spray products, but to all types of analytical testing as well. Third chapter provides insight into evaluation and comparison of average and population bioequivalence statistical approaches, using droplet size distribution and spray pattern in vitro tests. In vitro data were collected using a well-established nasal spray product on the market. Computationally intensive bootstrap simulations were used to evaluate both approaches. We concluded that both approaches can lead to different in vitro bioequivalence conclusion, especially in the case of highly variable spray pattern parameter, where pronounced asymmetric behavior of PBE empirical power curves was observed. Due to inherent high variability and unclear in vivo relevance of the spray pattern parameter, authors propose that this parameter is used as a development and quality control tool rather than for demonstration of in vitro bioequivalence. A modified PBE statistical approach is proposed for less variable droplet size distribution parameters, where acceptance criteria would be established based on comparison of reference/branded product to itself, using via innovative statistical bootstrap simulations. Most important contribution of this doctoral thesis is to provide insight into a modern and innovative approaches for time-cost efficient development of nasal spray products.
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