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Oligonucleotide Process Development

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Oligonucleotide Process Development

Design & Feasibility • Pilot Synthesis • Purification Optimization • Scale-Up • Analytical Methods • Formulation • Regulatory

Overview Design Pilot Synthesis Purification Scale-Up Analytics Formulation Regulatory Add-On Services Contact

Overview

Custom oligonucleotide process development is far more than linking bases — it’s a multi-step R&D and manufacturing pipeline that must balance chemistry, scalability, purity, and compliance, especially for therapeutic and diagnostic use.

At Bio-Synthesis, Inc., we deliver end-to-end solutions, transforming concepts into scalable, reproducible, and regulatory-ready processes. Our expertise covers DNA, RNA, LNA, PNA, Morpholino, and mixed-backbone chemistries, with decades of experience in integrating complex modifications, conjugates, and novel chemistries into robust workflows.

We guide projects from design and feasibility through pilot synthesis, purification optimization, scale-up, analytical validation, and formulation — all within a rigorous quality framework. Whether your goal is research-use, ISO13485, or GLP-compliant production, every step is data-driven and quality-controlled.

  • Complex and highly modified oligos, including rare/custom monomers
  • Integrated analytical capabilities: HPLC, LC-MS, CE, UV, stability studies
  • Flexible scale — from µmol R&D batches to multi-gram GMP lots
  • Full documentation and tech transfer for regulatory filings

At-a-Glance

  • Bioinformatics-assisted sequence & modification design
  • Pilot synthesis with real-time QC feedback (HPLC/MS/UV)
  • Purification route optimization (RP-HPLC, IEX, PAGE)
  • Process scaling for small to large production columns
  • ICH stability programs and validated analytical methods
  • Formulation development and sterile filtration for in vivo/IVD
  • Regulatory-ready documentation from COA to ISO13485 or GLPbatch records

Bio-Synthesis offers the rare combination of deep chemistry expertise, state-of-the-art facilities, and personalized technical support — ensuring your oligos are delivered exactly to spec, on time, and ready for their intended application.

Workflow

Oligo Process Development Workflow

1) Design & Feasibility

Sequence & Chemistry
  • Base/backbone selection with length/Tm constraints
  • Modification plan (e.g., 2′-OMe/2′-F, PS linkages, conjugation handles)
  • Protecting groups & coupling strategy compatibility
Synthetic Feasibility
  • Reagent availability vs. custom monomer development
  • Risk assessment: low-yield steps, sensitive linkers, scale risks
  • Initial process map and QC checkpoints
Bioinformatics
  • Specificity checks and off-target analysis
  • Secondary structure modeling (critical for siRNA/ASO)

2) Pilot Synthesis & Screening

Small-Scale Runs

Automated solid-phase synthesis (1–10 µmol) to evaluate coupling efficiency and stepwise yields.

  • Cycle timing, activators, capping, and oxidation/sulfurization
  • Early integration of non-standard bases, dyes, linkers
Rapid QC Feedback
  • Crude purity by HPLC/CE; identity by LC-MS
  • UV quantitation and molar extinction checks
  • Decision gates for purification route selection

3) Purification Process Development

Route Screening
  • RP-HPLC for hydrophobicity-driven separations
  • IEX for charge resolution of long/PS-rich oligos
  • PAGE for short oligos or ultra-high purity needs
Objectives
  • Removal of truncated sequences and deprotection by-products
  • Yield vs. purity trade-off curves and cycle-time targets
  • Solvent/gradient design scalable to prep columns
Case Preferred Method Notes
Short DNA (≤35 nt) RP-HPLC Fast cycles; strong resolution of truncateds
PS-rich ASO/Gapmer IEX Charge-based separation of isomers
siRNA Duplex RP-HPLC + Anneal Strand purification then duplexing

4) Scale-Up Development

Process Translation
  • Flow rates, reagent consumption, temperature profiles
  • Column loading, packing density, solvent recovery
  • Cycle-time modeling and throughput planning
Finishing & Stability
  • Drying: lyophilization or spray-dry, residual solvent testing
  • In-process controls and in-line analytics where applicable
  • Tech transfer package for manufacturing

5) Analytical Method Development

Identity & Purity
  • HPLC/UPLC, CE, and mass spectrometry fingerprints
  • Sequence-specific assays (hybridization, enzymatic)
  • Impurity profiling and reporting thresholds
Stability Programs
  • Accelerated/long-term per ICH guidance
  • Shipping/temperature excursion studies
  • Method validation (accuracy, precision, linearity, robustness)

6) Formulation & Delivery Readiness

Buffers & Formats
  • TE, PBS, or custom buffers; defined pH/ionic strength
  • Lyophilized cakes or liquid vials; tubes or plates
  • Sterile filtration and bioburden/endotoxin testing (as needed)
Conjugation Stability
  • Labels: dyes, biotin, peptides, lipids, GalNAc, PEG
  • Stress testing across storage/handling conditions
  • Functional assays to confirm activity post-formulation

7) Documentation & Regulatory

Standard Deliverables
  • COA with yield, purity, and identity data
  • HPLC traces and MS spectra
  • Sequence maps and formulation records
GMP Readiness
  • Batch records, raw-material traceability, QA oversight
  • Change control and deviation management
  • Documented tech transfer to manufacturing
Request a Development Plan

Optional Add-On Services

Barcoding & Pooling

Custom labels/barcodes, plate maps, and pool design for screens.

Plate Formatting

96/384-well plates, normalized concentrations, and QC stamps.

Blinded Studies

Sequence masking and third-party shipping coordination.

Need something not listed?

We routinely implement bespoke chemistries and workflows.

Get in Touch

How to Start

  1. Share sequence(s), application, and target product profile.
  2. Specify backbone/modifications and intended scale(s).
  3. Select desired purification and QC deliverables.
  4. Note formulation, packaging, and documentation needs.

Specs Checklist

  • Chemistry (DNA/RNA/LNA/PNA/etc.), length, and modifications
  • Purity targets and accepted impurity thresholds
  • Throughput (single to plate) and packaging format
  • Regulatory context (RUO, IVD, GLP, GMP)
Request a Quote

FAQ

What determines whether RP-HPLC or IEX is used?

Hydrophobic modifications and shorter oligos favor RP-HPLC; longer or PS-rich designs that differ by charge resolve better on IEX. We screen routes during pilot work.

Can you transfer the process to our site or a CMO?

Yes. We prepare a full tech-transfer package with parameters, specs, and in-process controls, and support on-site qualification if required.

Do you provide ICH stability data?

We run accelerated and long-term studies and generate protocols/reports aligned to ICH expectations for your filing context.

What QC is standard?

Analytical HPLC and MS identity are standard; additional methods (CE, sequencing/hybridization assays, endotoxin/bioburden) are available as needed.

Ready to develop a scalable oligo process?

Tell us your chemistry, scale, and purity targets—we’ll propose a phased plan with timelines and deliverables.

Request a Quote

Speak to a Scientist

Complete the form to receive a tailored quote. Your request will be emailed to info@biosyn.com and logged to your CRM endpoint (configure below).

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