US DMF#41707

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Impurity Study

Full characterization was performed against RLD, including FLP, CNET, ADP, IDP, N+P (mocG, mocA, moe meU, moe meC), N-P (mocG, mocA, moe meU, moe meC), 2'-MOE, 2'-O-EOE, Front elution, Post elution etc.

Sameness

  • Mass Spectrometry (MS/MS):
  • Determines the exact molecular weight of nusinersen to verify its chemical composition.
  • Tandem MS (MS/MS) fragments the oligonucleotide to confirm its sequence integrity and identify any impurities or degradation products.
  • Nuclear Magnetic Resonance (NMR) Spectroscopy:
  • Validates the three-dimensional structure of nusinersen, ensuring correct base pairing and backbone conformation.
  • Detects potential structural deviations or modifications.
  • Liquid Chromatography (LC):
  • Separates nusinersen from impurities, excipients, or process-related byproducts.
  • Quantifies purity and monitors stability under storage conditions.
  • Duplex Melting Temperature (Tm):
  • Measures the thermal stability of the duplex formed between nusinersen and its complementary RNA strand.
  • Reflects binding strength and hybridization efficiency, critical for its mechanism of action.
  • Circular Dichroism (CD) Spectroscopy:
  • Analyzes the secondary structure (e.g., A-form helix) of nusinersen.
  • Ensures proper folding and conformational stability.
  • Differential Scanning Calorimetry (DSC):
  • Assesses thermal stability by measuring heat absorption during structural transitions (e.g., denaturation).
  • Evaluates batch-to-batch consistency and formulation robustness.
  • Size Exclusion Chromatography (SEC):
  • Determines the oligonucleotide size distribution and detects aggregates or fragments.
  • Ensures nusinersen remains monomeric and within specified size limits.
  • Sedimentation Velocity Analytical Ultracentrifugation (SV-AUC):
  • Provides high-resolution analysis of molecular weight, shape, and aggregation state.
  • Validates homogeneity and confirms the absence of higher-order aggregates.


Documentation & Regulatory

US FDA compliance.