Oligonucleotide NCE process and CMC development
Chemistry, manufacturing and controls for oligonucleotide new chemical entities: route scouting on solid-phase synthesizers, impurity fate studies, specification setting, stability protocols and regulatory-ready documentation — without implying a specific plant configuration.
QTP
quality target profile
ICH
Q-series alignment
PS / 2'
modification lock
Forced deg
stability studies
IND
enabling package goal
What oligo CMC covers
Process development locks the synthetic route (amidite set, coupling chemistry, cleavage and deprotection), purification train (desalting, RP or ion-exchange, optional preparative HPLC), and formulation / salt form.
Analytical methods are qualified for identity, purity, impurities (length variants, modification isomers, low-molecular-weight by-products), residual solvents and water. Stability studies support proposed retest periods and shipping conditions for drug substance.
Indicative CMC phase timeline
Durations are program-dependent; phases often overlap rather than run strictly serial.
Route & impurity scouting
Manufacturing
Screen scales on synthesizer; map n–1/n+1; chiral PS where relevant
Analytics
Draft methods; forced degradation; impurity identification
Stability
Accelerated probes on research lots
Regulatory
Target profile discussion; pharmacopeial alignment check
Process characterization
Manufacturing
Define CPPs/CMAs; purification clearance of critical impurities
Analytics
Method robustness; system suitability; reference standard qualification
Stability
Formal stability protocol draft
Regulatory
Quality overall summary skeleton
Registration / clinical readiness
Manufacturing
PPQ or engineering batches at intended commercial scale band
Analytics
Validated release and stability methods
Stability
Long-term and accelerated per ICH
Regulatory
Module 3 text support; spec justification
Common CMC risk decisions
| Risk | Detection | Mitigation |
|---|---|---|
| PS diastereomer drift | HPLC envelope | Control coupling conditions; tighten release limits |
| n–1 truncation | IE-HPLC / MS | Optimize couplings; capping strategy; cut point in purification |
| Aggregation / G-quadruplex | SEC / native MS | Heat/cool handling; betaine in buffer; sequence redesign |
| Genotoxic impurity route | Amidite / solvent trace | Vice controls; solvent class limits per ICH M7 |
Figures are indicative industry-typical values. Lot- and project-specific data appear on the quotation and certificate of analysis.
Typical development documentation
Process description
Stage-appropriate P&ID narrative
Equipment agnostic in early phases
Control strategy
CPP / CQA map
Links to specification
Specifications
Draft → formal
Tighten from tox to clinical
Stability
ICH Q1A aligned
Drug substance primary
Comparability
Change control plan
Scale or site changes
Figures are indicative industry-typical values. Lot- and project-specific data appear on the quotation and certificate of analysis.
CMC service elements
Manufacturing science
- Scale-up from mg to kg (indicative band per quote)
- Purification train selection
- Salt form and lyophilization cycle development
Analytics
- Method development and qualification
- Reference standard establishment
- Forced degradation and impurity ID
Regulatory support
- Module 3 drafting support
- Specification justification memos
- Stability summary tables
What you receive
- Process development report with impurity fate summary
- Draft and final drug substance specification
- Qualified or validated analytical methods (per phase)
- Stability data tables and protocol
- Batch records for engineering / tox lots
- Regulatory documentation support as scoped in MSA
Frequently asked questions
Many teams begin route lock and impurity mapping at candidate nomination, before GLP tox material is ordered.
Related
Clinical & Commercial GMP
GMP manufacturing of oligonucleotide drug substance for clinical trials and commercial supply: batch records, validated release and stability methods, change control, and documentation packages suitable for regulatory filing — described at capability level without inventing facility certifications.
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View detailssiRNA Duplexes
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View detailsReady to specify this for your program?
Share sequence, scale and documentation needs. We reply with indicative specs and a project-specific quotation.