Evolving Challenges in Developing Naturally-Derived Complex Mixtures into Drugs: U.S. Experience and Perspective

Naturally-derived complex mixture drugs are the drugs derived from natural sources with highly heterogeneous molecular components. In such drugs, the composition of molecules in a population may be variable and it may even be difficult to define all components of a mixture. Even active components can be unknown or poorly characterized. As compared to traditional homogeneous drugs, these complex mixture drugs can face unique challenges during development and throughout the drug product lifecycle. As the understanding and science surrounding the analysis of these drugs advances, so too do the approaches to development. Scientific and regulatory approaches for these drugs may take into account prior human experience, current capabilities in characterization, ability to control raw material and manufacturing, therapeutic consistency, pharmaceutical equivalence, and bioequivalence. As more advanced analytics are developed and implemented, the ability to ensure the quality, safety, and efficacy of complex mixture drugs improves. This chapter introduces the major themes of development for these drugs including regulatory frameworks, biological activity, characterization, raw material and manufacturing control, impurities and immunogenicity, and clinical considerations. The challenges in developing natural-derived complex mixture drugs illustrate lessons of the past that can inform drug development in the future.