Regulatory Stipulations and Scientific Underpinnings for Inhaled Biologics for Local Action in the Respiratory Tract—Part II: A Characterization of Inhaled Biological Proteins

Following the discovery of therapeutic molecules and the identification of specific biological targets, preparation of regulatory dossiers entails extensive product development and characterization to support their safety, efficacy, and stability. We have examined the drug development and relevant regulatory considerations related to inhaled biological proteins in the accompanying article. This review focuses on the characterization of locally acting inhaled biological proteins. Drug product characterization is a regulatory requirement, and it ensures drug product safety, efficacy, stability, and usability by the target populations. Together, these two articles provide a comprehensive discussion based on our review and analysis of the available open literature. We have attempted to fill gaps and simulate discussion of challenges following sound scientific pathways. This approach has the prospect of addressing regulatory expectations leading to rapid solutions to unmet medical needs. The robustness of characterization strategies and the development of analytical methods used in the in vitro testing for the evaluation of drug product attributes is assured through application of the Design-of-Experiment (DOE) and Quality-by-Design (QBD) approaches. Drug product characterization entails a variety of in vitro studies evaluating drug products for purity and contamination, and determination of drug delivery by the intended route of administration. Measurement of the proportion of the labeled amount per dose and the form suitable for delivery to the intended target sites is central to this assessment. For respiratory Drug–Device combination products, the testing may vary with the product designs. However, determination of the single-dose content, delivered-dose uniformity, aerodynamic particle size distribution, and device robustness when used by the target populations is common to all combination products. Characterization of aerosol plumes is limited to inhalation aerosols that produce specific aerosol clouds upon actuation. The flow rate dependency of devices is also examined. Product characterization also includes safety-related product attributes such as degradation products and leachables. For inhaled biological proteins, safety-related in vitro testing includes additional testing to assure maintenance of the three-dimensional structural integrity and the sustained biological activity of the drug substance in the formulation, during aerosolization and upon deposition. This article discusses various tests employed for regulatory-compliant product characterization. In addition, the stability testing and handling of possible changes during product development and post-approval are discussed.