title: Challenges in the pharmaceutical development of lipid-based short interfering ribonucleic acid therapeutics.
abstract: BACKGROUND
  Harnessing RNA interference as a therapeutic approach has the potential to significantly expand the druggable target space, offering new hope for treatment of diseases that cannot be addressed with existing classes of drugs. A number of siRNA therapeutics have already progressed into preclinical and clinical development. Of these, lipid-based systems have emerged as one of the most mature classes of systemic delivery technologies. Despite tremendous advances in development, a number of significant challenges must still be addressed to enable commercialization of a lipid-based siRNA pharmaceutical product.
  
  
  METHODS
  This review addresses specific challenges inherent to the pharmaceutical development of lipid-based siRNA therapeutics. Focus is placed on the development of a robust manufacturing process, the setting of appropriate product specifications and controls, development of strategies to assess and ensure product stability, and the evaluation of product comparability throughout development.
  
  
  CONCLUSIONS
  Discovering and developing a lipid-based siRNA therapeutic that can be commercialized requires engineering a particle that selectively and efficiently delivers the cargo to the target tissue and cellular compartment. The particle assembly must be strictly controlled and physical properties thoroughly characterized to successfully develop an understanding of particle attributes that influence in vivo pharmaceutical properties. Correlation of particle physio-chemical properties to product performance is the foundation for advancements in discovery and assuring quality in a commercial drug product. Although difficult, we believe these development challenges can be addressed with appropriate scientific resources and that the industry will continue to progress siRNA therapeutic candidates through clinical development.
authors.affiliation: Department of Pharmaceutical Sciences, Merck Research Laboratories, Merck, PA, USA. marian_gindy@merck.com
authors.forename: Marian E
authors.initials: ME
authors.lastname: Gindy
authors.forename: Anthony M
authors.initials: AM
authors.lastname: Leone
authors.forename: James J
authors.initials: JJ
authors.lastname: Cunningham
mesh_terms: D002626:Chemistry, Pharmaceutical / Q000379:methods; D016503:Drug Delivery Systems; D055808:Drug Discovery; D004355:Drug Stability; D006801:Humans; D008055:Lipids / Q000008:administration & dosage / Q000737:chemistry; D053758:Nanoparticles / Q000008:administration & dosage; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000008:administration & dosage* / Q000737:chemistry*; D013678:Technology, Pharmaceutical
chemical_list: D008055:Lipids; D034741:RNA, Small Interfering