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siRNA based therapeutics is an emerging class of molecules with a high potential for fulfilling the promise of gene medicine. The high selectivity of siRNAs for their targets and subsequent gene ablation has been effectively demonstrated in a wide range of pre-clinical models. siRNA delivery in vivo has been most successfully achieved using lipid-based drug delivery systems. These lipid based formulations are designed to entrap siRNA molecules, ensure stability in in vitro and in vivo milieu, facilitate uptake, enhance cellular targeting, and facilitate delivery in the desired intracellular compartment. As more siRNA-based therapeutics enters the clinic with the associated regulatory scrutiny, there is a clear need to develop well-characterized systems that ensure consistent quality and thus reliable performance. Early clinical trials can be conducted using formulations with limited short-term stability manufactured on a small scale. However, a thorough understanding of the factors that influence the structure and stability of these particulate formulations is required to prevent any issues with optimization of large-scale industrial manufacturing, scale-up, and long-term shelf-life required to support large clinical trials and eventual market use. As newer targets for siRNA are identified and novel lipids are synthesized to optimize their in vivo efficiency, concomitant development of bio-physical methodologies that can improve understanding of the assembly and stability of these complex systems is critical. Along with bio-physical characterization, these assays are also required to reliably design, screen, develop and optimize formulations. Physicochemical characterization thus forms the basis of developing an effective analytical control strategy for siRNA delivery systems. In this review, analytical techniques used to characterize lipid-based siRNA delivery systems are discussed in detail. The importance of these physicochemical characterization techniques and analytical assays is explained. Case studies illustrating their use in siRNA formulation development and optimization are presented.