This volume in the AAPS Advances series covers various quality, safety and clinical aspects of drug development that are relevant to new and/or generic drugs containing a complex mixture of molecules. Specific topics discussed include: raw materials sourcing; manufacturing controls; characterization; identification of critical product quality components and attributes; identification of impurities, particularly as they bear on toxicity and immunogenicity; clinical trial study design considerations, and the regulatory science applications to development of such complex mixtures. Complex mixtures are challenging to characterize and analyze using standard methods. Further challenges extend throughout the product development cycle from raw material control to clinical study design. The regulatory landscape is rapidly changing as new types of complex mixtures are introduced into clinical trials and to the market (e.g., traditional Chinese medicines and medical marijuana products), while older products are facing generic competition for the first time (e.g., enoxaparin). The future outlook for complex generic drug products, as opposed to the more commonly developed targeted single agent drug products is not clear. The risks pertaining to lack of a full understanding of raw material control, process and controls in manufacture, as well as characterization of a complex mixture were seen vividly during the heparin crisis of 2008. As such powerful lessons have been learned about the regulatory science specific to complex products. The Science and Regulations of Naturally Derived Complex Drugs addresses the interests among industry, academics, and government on the issues surrounding the future development of mixtures for medicinal use.

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

Regulatory Landscapes for Approval of Naturally-derived Complex Mixture Drugs
Complex Natural Product Heparin: Biosynthesis, Biology and Application via Synthetic Heparins
Traditional Chinese Medicine Herbal Drugs: From Heritage to Future Developments
Analytics on Farm-Dust Extract for Development of Novel Strategies to Prevent Asthma and Allergic Disease
Analytical Tools for Physicochemical Characterization and Fingerprinting
NMR in the Characterization of Complex Mixture Drugs
Mass Spectrometry in the Characterization of Complex Drugs
Scientific Considerations in the Approval of Complex Generi
Raw Materials Production and Manufacturing Process Control Strategies
Heparin Contamination and Issues Related to Raw Materials and Controls
Pharmacology and Toxicology Concerns of Impurities
Immunogenicity risks for Naturally Derived Complex Drugs
Development of Plant-Derived Mixtures as Botanical Drugs: Clinical Considerations
A Totality-of-Evidence Approach to Ensuring Therapeutic Consistency of Naturally Derived Complex Mixtures
Economic Considerations for Complex Mixture Drugs
Drug Discovery from Complex Mixtures: Serendipity, Screening and Characterization
Integrated Approach for Characterization of Highly Heterogeneous Drugs.