Prediction of protein degradation during vibrating mesh nebulization via a high throughput screening method

• Material-saving method to predict protein stability after nebulization developed.
• Detrimental conditions of vibrating mesh nebulization mimicked by agitation, heating.
• Surrogate method predicts impact of excipient concentration on protein stability.
• Inhalable protein formulation developed with the surrogate method and DoE.

Maintaining the integrity of biopharmaceuticals is a major requirement for successful pulmonary delivery by nebulization. Sparing laborious nebulization tests, this study aimed to demonstrate the feasibility of a high throughput, material saving surrogate method to predict protein stability after nebulization. Detrimental conditions during nebulization with a PARI eFlow® vibrating mesh nebulizer were mimicked by vigorous agitation at elevated temperatures. Comparing the effect of several different excipients on the stability of the protein SM101 after nebulization and after the surrogate method revealed an excellent correlation regarding SM101 aggregation (R2 = 0.97). Design of experiment was used to develop an inhalable formulation of SM101 based entirely on the new surrogate method. Two lead formulation candidates were selected based on their predicted stability profile. The conservation of full SM101 stability and activity after nebulization was confirmed for an AKITA2 vibrating mesh nebulizer. This study demonstrated that biopharmaceutical formulation development for nebulization is feasible by means of imitating nebulizer related detrimental factors, allowing an accelerated and more economic formulation development.

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