Current CMC challenges in oligonucleotide API development: from IND to NDA
Daoqian Chen1, Xiaobing Zhang2, Songgen Xu3
1Chemical Pharmaceutical Research Center, Changchun GeneScience Pharmaceutical Co., Ltd, Shanghai, 200120, P.R. China. chendaoqian0203@gmail.com.
Abstract:
Oligonucleotide therapeutics are becoming representatives of the "Third Wave" of pharmaceutical innovation, expending from initial rare diseases to oncology and chronic indications, following small molecules and proteins. Globally, hundreds of clinical trials are currently underway, in addition to the 26 oligonucleotide drugs that have already been approved. Although nearly thirty years have elapsed since the initial approval of Fomivirsen, oligonucleotide therapeutics continue to pose unique CMC (Chemistry, Manufacturing, and Controls) challenges that are distinct from small molecules. Furthermore, the lack of harmonized ICH guidelines specifically for oligonucleotides forces developers to navigate a "regulatory grey area" between new molecular entities (NMEs) and biologics. This perspective focuses on the technical and regulatory hurdles of API (Active Pharmaceutical Ingredient) CMC development, covering synthesis (including conjugation strategies with delivery systems), analysis and regulatory aspects, with a specific emphasis on stage-appropriate requirements from the Investigational New Drug (IND) application to the New Drug Application (NDA).
Insights
Oligonucleotide therapeutics face unique Chemistry, Manufacturing, and Controls (CMC) challenges distinct from small molecules. This perspective details API CMC development hurdles from Investigational New Drug (IND) to New Drug Application (NDA).
Area of Science:
- Pharmaceutical Sciences
- Drug Development
- Regulatory Science
Background:
- Oligonucleotide therapeutics represent a significant advancement in pharmaceutical innovation, expanding beyond rare diseases to oncology and chronic conditions.
- Over 26 oligonucleotide drugs are approved, with hundreds more in clinical trials, highlighting their growing importance.
- Despite their success, oligonucleotide therapeutics present unique Chemistry, Manufacturing, and Controls (CMC) challenges distinct from traditional small molecules.
Purpose of the Study:
- To provide a comprehensive overview of the technical and regulatory hurdles in Active Pharmaceutical Ingredient (API) CMC development for oligonucleotide therapeutics.
- To emphasize stage-appropriate CMC requirements throughout the drug development lifecycle, from Investigational New Drug (IND) to New Drug Application (NDA).
- To address the challenges posed by the lack of harmonized International Council for Harmonisation (ICH) guidelines for oligonucleotides.
Main Methods:
- Discussion of synthesis strategies, including conjugation with delivery systems.
- Analysis of critical quality attributes and analytical method development for oligonucleotide APIs.
- Exploration of regulatory pathways and considerations for oligonucleotide drug development.
Main Results:
- Oligonucleotide CMC development requires specialized approaches for synthesis, purification, and characterization.
- Navigating regulatory requirements involves addressing a 'grey area' between New Molecular Entities (NMEs) and biologics.
- Stage-appropriate CMC strategies are crucial for successful progression from early-stage development to market approval.
Conclusions:
- Addressing the unique CMC challenges of oligonucleotide therapeutics is essential for efficient drug development.
- Clearer regulatory guidance and harmonized standards would benefit the field.
- Successful navigation of technical and regulatory hurdles is key to realizing the full potential of oligonucleotide-based medicines.
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