The Science and Regulations of Naturally Derived Complex Drugs

1. Front Matter

   Pages i-vi

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

   • Adam C. Fisher, Sau L. Lee

   Pages 1-15

3. Regulatory Landscapes for Approval of Naturally-Derived Complex Mixture Drugs

   • Larisa C. Wu, Andre Raw, Werner Knöss, Michael Smith, Wei-Dong Zhang, Y. S. Bedi et al.

   Pages 17-44

4. Complex Natural Product Heparin: Biosynthesis, Biology, and Application via Synthetic Heparins

   • Po-Hung Hsieh, Jian Liu

   Pages 45-58

5. Traditional Chinese Medicine Herbal Drugs: From Heritage to Future Developments

   • Tai-Ping Fan, Yingli Zhu, Christine Leon, Gerhard Franz, Andreas Bender, Xiaohui Zheng

   Pages 59-77

6. Analytics on Farm Dust Extract for Development of Novel Strategies to Prevent Asthma and Allergic Disease

   • Nathan Stebbins, Erika von Mutius, Ram Sasisekharan

   Pages 79-90

7. Analytical Tools for Physicochemical Characterization and Fingerprinting

   • David A. Keire

   Pages 91-113

8. NMR in the Characterization of Complex Mixture Drugs

   • Marco Guerrini, Timothy R. Rudd, Edwin A. Yates

   Pages 115-137

9. Mass Spectrometry in the Characterization of Complex Drugs

   • Sarah Rogstad, Michael Boyne, Ashley Ruth

   Pages 139-155

10. Scientific Considerations in the Approval of Complex Generics

    • Andre S. Raw, Larisa Wu

    Pages 157-173

11. Raw Materials Production and Manufacturing Process Control Strategies

    • Suman Chandra, Donald Stanford, Edward Fletcher, Larry A. Walker

    Pages 175-190

12. Heparin Contamination and Issues Related to Raw Materials and Controls

    • Yuanyuan Zhu, Fuming Zhang, Robert J. Linhardt

    Pages 191-206

13. Pharmacology and Toxicology Concerns of Impurities

    • Daniel S. Marsman, Amy L. Roe

    Pages 207-217

14. Immunogenicity Risks for Naturally Derived Complex Drugs

    • Roshni Rao, Daniela Verthelyi

    Pages 219-244

15. Development of Plant-Derived Mixtures as Botanical Drugs: Clinical Considerations

    • Jinhui Dou, Julie Beitz, Robert Temple

    Pages 245-264

16. A Totality-of-Evidence Approach to Ensuring Therapeutic Consistency of Naturally Derived Complex Mixtures

    • Sau L. Lee

    Pages 265-270

17. Economic Considerations for Complex Mixture Drugs

    • Sen Lin

    Pages 271-295

18. Drug Discovery from Complex Mixtures: Serendipity, Screening, and Characterization

    • Melissa Jacob, Xing-Cong Li, Larry A. Walker

    Pages 297-310

19. Integrated Approach for Characterization of Highly Heterogeneous Drugs

    • Rahul Raman, Zachary Shriver, Thomas Clark, Ram Sasisekharan

    Pages 311-327

20. Back Matter

    Pages 329-331

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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.

• complex mixtures
• toxicity
• immunogenicity
• drug manufacturing
• single agent drug
• plant-derived natural products

• Department of Biological Engineering, Koch Institute of Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, USA

  Ram Sasisekharan

• Office of Pharmaceutical Quality, Center for Drug Evaluation and Research, Food and Drug Administration, Silver Spring, USA

  Sau L. Lee, Amy Rosenberg

• Director Emeritus, National Center for Natural Products Research, School of Pharmacy, University of Mississippi, Oxford, USA

  Larry A. Walker

Amy Rosenberg received her medical degree from Albert Einstein College of Medicine and is Board Certified in Internal Medicine. She was a post-doctoral fellow in Al Singer’s Laboratory in the NCI before coming to CBER, FDA in 1988. She became Director of the Division of Therapeutic Proteins, CBER/CDER in 2000. Her division (now DBRR3 in the Office of Biotechnology Products, CDER) regulates diverse protein therapeutics, including monoclonal antibodies and fusion proteins, enzyme replacement therapies, hematologic and somatic cell growth factors, and immunomodulatory agents. She has been a driving force in risk evaluation and mitigation pertaining to the immunogenicity of therapeutic proteins (Guidance for Industry: Immunogenicity Assessment for Therapeutic Protein Products) and in the elucidation and implementation of immune tolerance induction protocols in clinical settings. She previously co-edited the AAPS/Springer Book “Biobetters: Protein Engineering to Approach the Curative”. 

Larry A. Walker is Director Emeritus of the National Center for Natural Products Research (NCNPR) at the University of Mississippi, having retired at the end of 2016 after 15 years as director.  He has been a member of the faculty of the School of Pharmacy at Ole Miss for 37 years.  He took his undergraduate pharmacy training at Mercer University (1975), and his doctorate in Pharmacology from Vanderbilt University School of Medicine in 1979, He has worked for much of his career on natural products drug discovery, pharmacology, toxicology and metabolism. Dr. Walker is a co-author of more than 200 papers in peer-reviewed journals in pharmacology, toxicology, and natural products discovery and development.  He is a member of the American Society of Pharmacognosy, American Society of Pharmacology and Experimental Therapeutics, American Society of Microbiology, American Society of Tropical Medicine and Hygiene, American Association of Pharmaceutical Scientists. He has served on editorial boards of the Journal of Pharmacology and Experimental Therapeutics, Phytotherapy Research, and was the editor-in-chief of the Journal of Biomolecular Screening from 1999-2007. He received the University’s second Distinguished Research and Creative Achievement Award in 2009, and the School of Pharmacy’s Researcher of the Year Award in 2003.  He works presently on development of strategic partnerships for the University of Mississippi, and as a senior science advisor with ElSohly Laboratories, Inc. in Oxford, MS, and consultant for pharmaceutical and botanical supplement industries.  

 

 

 

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