Oligonucleotides

Method Development: Develop customized and robust method development strategies tailored to the structural characteristics of oligonucleotides (e.g., sequences, modifications) in reference to ICH Q14.

Method Validation: Perform comprehensive validation (e.g., specificity, accuracy, linearity, LOD/LOQ, etc.) in accordance with ICH Q2(R1) and pharmacopoeias to ensure compliance of release and stability indicating methods.

Method Transfer: Develop transfer protocols (comparative testing, co-validation) to ensure reliable performance of methods across different laboratories.

Method Optimization and Troubleshooting: Resolve challenges with clients’ existing methods or optimize performance.

Accurate molecular weight determination (including sequence length, base composition, modification types)

Sequence confirmation to verify the nucleotide arrangement order

Base composition analysis to verify that the molar ratios of native and modified bases (e.g., methylcytosine, pseudouridine, etc.) in oligonucleotides are consistent with theoretical values.

Terminal structure confirmation to verify the correct and complete attachment of modifying moieties (protecting groups, linkers, reporter groups, capping groups, etc.).

Backbone modification confirmation to verify the type, quantity and distribution of phosphodiester backbone modifications (e.g., phosphorothioate).

Stereostructure analysis, such as phosphorothioate linkages, stereochemical configuration of L nucleosides

Physical property study, e.g., osmotic pressure, solubility, pH value, hygroscopicity.

Identification and Sequence Confirmation: molecular weight, sequence, chromatographic behavior, base composition analysis, etc.

Purity and impurity analysis: main peak purity, impurity profile (process impurities such as short chain and long chain oligonucleotides, failure sequences, incomplete removal of protecting groups, incomplete phosphorylation products, phosphorothioate oxidation / isomerization products), degradation impurities (such as depurination, strand breaks, oxidation, desulfurization, etc.)

Assay determination

Biological activity

Other Tests: e.g., appearance, water content, residue on ignition, inorganic ions/elemental impurities, residual solvents, reagent residues, solution clarity and color, pH, osmotic pressure, etc.

Microbiological Testing: bioburden (complying with USP/EP/Ch.P standards), bacterial endotoxins (gelclot LAL assay, kinetic turbidimetric method and recombinant Factor C technology), etc.

Calibration of Primary Reference Standard

Preparation, calibration and management of Working Reference Standard

Isolation, purification, identification and calibration of impurity reference standards

Design and execute stability study protocols (accelerated, long term, intermediate conditions) in compliance with ICH Q1A (R2)

Provision of Stability Indicating Methods

Periodic testing of critical quality attributes (CQAs) to evaluate degradation pathways and rates

Prepare professional stability study reports to support IND/NDA filings

Solid data integrity foundation: in compliance with ALCOA principles (including computerized systems, electronic data and paper records)

Sound quality management system: a management system built based on cGMP regulations, including deviation, change control, OOS/ATR processes, internal audits and supplier management.

Extensive audit experience