type: news

title: Alnylam RNAi Product Approvals Timeline 2018–2025 (Onpattro/Givlaari/Oxlumo/Leqvio/Amvuttra/Rivfloza/Qfitlia)

venue: Alnylam Pharmaceuticals Press Releases

key_claim: Seven GalNAc-siRNA drugs approved FDA 2018–2025; Qfitlia approved March 2025 completing P5x25 strategy

conflict_of_interest: Company press release — authoritative for approval dates but authored by Alnylam

notes: Primary FDA approval chronology corroborated across multiple independent sources including biochempeg.com table and PMC clinical review


title: Arrowhead Pharmaceuticals Initiates Phase 1/2a Study of ARO-DIMER-PA – the First Dual Functional RNAi Therapeutic for Mixed Hyperlipidemia

venue: Arrowhead Pharmaceuticals Press Release

key_claim: ARO-DIMER-PA (PCSK9+APOC3) is first clinical-stage dual-functional RNAi molecule, Phase 1/2a initiated 2025

conflict_of_interest: Company-authored press release; clinical phase initiation fact is independently verifiable via ClinicalTrials.gov

notes: TRiM platform dual-target molecule; NHP preclinical data cited internally


title: Accelerating Dual-Target Small Nucleic Acid Therapeutics with Humanized Models

venue: Biocytogen Blog

key_claim: UK Biobank data: combined APOC3+PCSK9 protective alleles confer 10% lower CHD risk vs single allele (citing Wang et al. 2025)

conflict_of_interest: Commercial vendor blog; Wang et al. 2025 primary citation not directly accessed

notes: The 10% CHD risk reduction figure requires primary source verification against Wang et al. 2025 UK Biobank publication


type: journal

title: Development, opportunities, and challenges of siRNA nucleic acid drugs

venue: Molecular Therapy Nucleic Acids

key_claim: Six siRNA drugs commercially approved by 2025; clinical trial table includes complement C5 program cemdisiran in Phase 3

conflict_of_interest: None disclosed

notes: Open access Cell/Elsevier review; good pipeline table for confirmation of Phase status; used in Ch09 to confirm all approved GalNAc-siRNA drugs used batch solid-phase synthesis


type: report

title: Fast-Track to Phase I: Two siRNA IND CMC Packages Completed in 14 Months

venue: TIDES Conference / WuXi AppTec

key_claim: Standard GalNAc-siRNA GMP optimization: initial yield 13%/crude purity 18% improved to 62%/75% after process development; 500g GMP batch in 10 months

conflict_of_interest: CDMO-authored case study; WuXi AppTec has commercial interest in favorable presentation

notes: Technical detail level suggests genuine process disclosure not purely promotional; specific numbers used in Ch01 for baseline yield quantification


title: Refined Design and Liquid-Phase Assembly of GalNAc-siRNA Conjugates: Comparative Efficiency Validation in PCSK9 Targeting

venue: Molecules (MDPI)

key_claim: Commercial GalNAc-preloaded CPG supports have loading below 100 µmol/g hindering industrial-scale synthesis; liquid-phase synthesis enables gram-to-kg scale potential

notes: Same paper indexed as src_A03/src_B04/src_C01 in initial scan — used here specifically for CPG loading limitation quote; peer-reviewed primary synthesis paper


title: GalNAc siRNA Formulation for Liver Targeting — Technical Overview

venue: BOC Sciences Technical Notes

key_claim: GalNAc cluster as phosphoramidite monomer extends coupling cycle time from 2 min to 6 min due to diffusion limitations in 500 Å CPG pores

conflict_of_interest: Commercial vendor; cycle-time claim may derive from unpublished internal data

notes: Cycle-time figure flagged as requiring primary source verification; used only in Ch01 as a directional indicator with appropriate confidence level


type: database

title: BeBetter Med — Drug pipelines and Clinical Trials (Synapse/Patsnap)

venue: Patsnap Synapse Database

key_claim: BEBT-701 (AGT+PCSK9) NCT07368608 Phase 1/2 trial registered; start date January 26 2026; sponsor BeBetter Med

conflict_of_interest: Database aggregator, no inherent conflict

notes: NCT number and start date confirmed from ClinicalTrials.gov registry via Synapse aggregation


title: Durability and efficacy of solbinsiran, a GalNAc-conjugated siRNA targeting ANGPTL3, in adults with mixed dyslipidaemia (PROLONG-ANG3)

venue: The Lancet

key_claim: Solbinsiran Phase 2 PROLONG-ANG3: 205 patients, variable apoB reductions (significant only at 400 mg); 100 mg and 800 mg arms missed primary endpoint — illustrating variable single-target outcomes

conflict_of_interest: Eli Lilly-sponsored trial; declared industry conflicts among investigators

notes: Primary counter-evidence for Section CE01; Lancet publication score elevated despite COI because the COI is declared and trial was randomized controlled


title: Dual-targeting siRNAs could treat complex genetic diseases

venue: Bioxconomy

key_claim: Dual-target siRNAs present doubled off-target risk surface; 'careful safety evaluation will be essential in future translational studies' (citing Sugimoto et al.)

conflict_of_interest: Independent science journalism; Sugimoto primary citation not directly accessed

notes: Counter-evidence source CE02; primary Sugimoto publication should be located for stronger citation in Ch01 future revision


title: Alnylam R&D Day 2025 — GEMINI platform preclinical data (ANGPTL3+AGT dual siRNA single entity)

venue: Alnylam Pharmaceuticals R&D Day

key_claim: GEMINI combines two siRNAs in a single chemical entity; GEMINI-CVR targets ANGPTL3+AGT with biannual dosing goal; preclinical data show superior dual knockdown vs mixture

conflict_of_interest: Company R&D Day; technical content primary; corroborated by 10-K SEC filing

notes: Alnylam 2024 10-K (alny-20241231) independently corroborates GEMINI platform description and pre-IND status


title: Suzhou Ribo Life Science — Core Pipeline (RBD4059 Phase 2, RBD5044 Phase 2, RBD7022 Phase 2)

venue: Ribo IR / HKEX 06938

key_claim: 7 clinical-stage single-target assets; dual-target in active R&D under RiboGalSTAR™; no dual-target IND as of April 2026

conflict_of_interest: Company IR page; corroborated by ESC 2025 presentations and pharmaphorum independent coverage

notes: Ribo IPO raised HKD 1.59B on HKEX Jan 2026; pipeline page is real-time updated


title: Ribo ESC 2025 — RBD5044 Phase I: 84% APOC3 knockdown sustained at 6-month follow-up; RBD7022 Phase I: 75% PCSK9 max reduction at 6 months

venue: Ribo Press Release / ESC 2025

key_claim: RBD5044 single injection: 84% APOC3 knockdown sustained through 6-month follow-up; supports Q6M dosing; well-tolerated

conflict_of_interest: Company press release; clinical data presented at peer-reviewed conference (ESC 2025)

notes: ESC 2025 presentation is independent conference review; multiple Ribo assets presented same day


title: 2026最热：小核酸龙头来了 — Ribo IPO strategy and dual-target R&D roadmap

venue: China Medical Innovation Association (phirda.com)

key_claim: Ribo explicitly prioritizes dual-target and multi-target technology breakthroughs; RSC 2.0 modification system; RiboGalSTAR™ liver delivery

conflict_of_interest: Association publication; corroborates HKEX prospectus language; dual-target R&D priority confirmed

notes: Used for strategic context only; Ribo HKEX prospectus is the primary source for dual-target R&D priority claim


title: RNA specialist Ribo files $205m IPO in Hong Kong — 7 clinical assets, dual-target in R&D

venue: pharmaphorum

key_claim: Ribo HKD 1.59B IPO; 7 clinical-stage assets; Boehringer Ingelheim MASH + Qilu dyslipidaemia partnerships >$2B combined; RiboGalSTAR™ dual-target extension in development

conflict_of_interest: Independent trade press (pharmaphorum); no conflict; corroborates HKEX prospectus data

notes: Pharmaphorum is Tier 2 trade media; independent confirmation of Ribo pipeline and partnership data


title: Argo Biopharma: BW-00163 (AGT siRNA) advances to Phase 2; Novartis milestone payment; $4B+ total deal value

venue: Argo Biopharma Press Release

key_claim: BW-00163 progressed to Phase 2 via Novartis June 2025; $185M upfront + $4B+ total potential from Jan 2024 deal for two cardiovascular assets

conflict_of_interest: Company press release; deal terms independently referenced in VCBeat and Novartis regulatory filings

notes: NCT06857955 (BW-00163 Phase 2 Novartis-sponsored) independently registered on ClinicalTrials.gov


title: Argo Biopharma doses first patients in Phase II trials of BW-40202 (CFB siRNA, PNH + IgAN)

venue: PR Newswire / Argo Biopharma

key_claim: First patient dosed April 20, 2026 in Phase II BW-40202 trials for PNH and IgAN; BW-40202 is single-target CFB siRNA; RADS™ platform

conflict_of_interest: Company press release on PR Newswire; independently corroborated by CTR20252839 registry

notes: Very recent (April 20, 2026); confirmed in both NMPA ChiCTR registry and Australian IND registry


title: Sirnaomics Pipeline — muRNA dual-target programs STP271G (PCSK9+ANGPTL3), STP237G (AGT+APOC3), STP247G (CFB+C5)

venue: Sirnaomics (HKEX 2257)

key_claim: Sirnaomics has 3+ preclinical muRNA dual-target programs; PDoV-GalNAc scaffold also preclinical; muRNA design confirmed as single-molecule by RSC Med Chem 2025

conflict_of_interest: Company pipeline page; muRNA architecture independently described in RSC Medicinal Chemistry review 2025

notes: PDoV-GalNAc and GalAhead™ muRNA are distinct Sirnaomics scaffolds; both preclinical for dual-target programs


title: 迈威生物 (688062) 2MW7141 dual-target siRNA licensed to Kalexo Bio; ≤$1B deal value

venue: Securities Times (STCN) / Shanghai STAR Market regulatory disclosure

key_claim: 2MW7141 is preclinical-stage dual-target siRNA for lipid abnormalities; ≤$1B deal with Kalexo (Aditum Bio); target identity undisclosed; first-in-class non-LNP delivery claimed

conflict_of_interest: STCN aggregates Shanghai STAR Market regulatory disclosures; 688062 is publicly listed company; deal terms are formal disclosure

notes: STCN (Securities Times) is official SHEX disclosure channel; deal value constitutes mandatory regulatory disclosure for listed company


title: China's Biotech Push Into Small Nucleic Acid Drugs Draws Global Pharma (Caixin Global Feb 2026)

venue: Caixin Global

key_claim: Over 100 Chinese small nucleic acid drug pipelines by Jan 2026 (Insight data); global siRNA market $2.7B (2019) to $5.7B (2024); >$36B in 2025 sector transactions

conflict_of_interest: Caixin is independent financial journalism; data attributed to Huaxi Securities and Insight database

notes: Caixin is premium financial media with editorial standards; the 100+ pipeline figure should be treated as directional (definitionally broad)


title: Disulfide-Containing Parenteral Delivery Systems and Their Redox-Biological Fate

venue: Journal of Controlled Release

key_claim: Intracellular GSH 1–10 mM; extracellular plasma GSH ~2–20 µM; ~500-fold gradient drives selective intracellular disulfide cleavage for siRNA delivery

conflict_of_interest: None disclosed; academic review

notes: Foundational redox biology review; mechanism unchanged since publication; score adjusted for age (-0.6 recency penalty for 12-year-old paper in stable-mechanism category)


title: Analysis of siRNA with Denaturing and Non-Denaturing Ion-Pair Reversed-Phase Liquid Chromatography Methods

venue: LCGC International

key_claim: Denaturing IP-RPLC separates hetero-duplex, homo-duplex, and single-strand populations in dual-siRNA constructs; method validation requirements described

conflict_of_interest: None disclosed; analytical methods article

notes: Professional analytical methods journal; specific siRNA duplex separation method validation described; supports hetero-duplex QC claim for covalent tandem paradigm


title: Targeted delivery of oligonucleotides using multivalent protein-carbohydrate interactions

venue: Chemical Society Reviews (RSC)

key_claim: Alnylam triantennary GalNAc Kd = 2.3 nM for ASGPR; 10^6-fold affinity gain from mono to triantennary; tetraantennary only modest further improvement; cluster effect mechanism

conflict_of_interest: None disclosed; independent academic review

notes: Chem Soc Rev high IF; comprehensive review of multivalent carbohydrate-ASGPR binding; Kd = 2.3 nM value confirmed from Nair et al. JACS 2014 primary data cited within


type: regulatory

title: ICH Q6A — Specifications: Test Procedures and Acceptance Criteria for New Drug Substances and Drug Products (Chemical Substances)

venue: ICH / FDA / EMA

key_claim: Specifications framework for drug substance identity and purity; mixture-API composition ratio control requirements; <5% CV inference for fixed-composition mixture products

conflict_of_interest: None; regulatory guidance

notes: Still-authoritative ICH guidance; specific <5% CV figure for siRNA cocktail composition is inferred not explicitly stated — flagged as unverified in evidence table C15; recommend FDA OPQ consultation


title: Evaluation of GalNAc-siRNA Conjugate Activity in Pre-clinical Animal Models with Reduced Asialoglycoprotein Receptor Expression

venue: Molecular Therapy Nucleic Acids

key_claim: Triantennary GalNAc-ASGPR Kd ~2 nM; ASGPR receptor saturation documented at doses >5 mg/kg; in silico model parameters: Kd=2nM, kon=1e5 M-1s-1, ASGPR ~600 nM intrahepatic

conflict_of_interest: Alnylam-affiliated authors; declared; data directly relevant and specific

notes: Key quantitative ASGPR saturation data; Kd value corroborates src_E13; saturation threshold at >5 mg/kg provides basis for cocktail receptor saturation counter-argument; COI declared and methodology sound


title: Acetonitrile Regeneration from Oligonucleotide Production Waste

venue: Organic Process Research & Development (ACS)

key_claim: Approximately 85% of total acetonitrile usage in SPOS is consumed during synthesis wash steps

conflict_of_interest: None disclosed

notes: ACS OPR&D primary paper on solvent use in oligo manufacturing; 85% stat is key for PMI analysis


title: Solid-Phase Oligonucleotide Synthesis (SPOS) and Liquid-Phase Oligonucleotide Synthesis (LPOS): A Comparative Review

venue: SynerG BioPharma White Paper

key_claim: PMI for 20-mer therapeutic oligos: 3,035–7,023 (avg 4,299); MeCN consumption up to 1,000 kg/kg API; AJIPHASE 21-mer siRNA: 60% yield, >90% purity

conflict_of_interest: CDMO-affiliated white paper; PMI data cites published sources; AJIPHASE claim cites Ajinomoto

notes: Useful aggregator of SPOS/LPOS comparative data; primary sources should be traced where possible


title: Biochemical and structural insights into a 5' to 3' RNA ligase — T4 RNA Ligase 1 substrate requirements

venue: PMC / Nucleic Acids Research

key_claim: T4 RNA Ligase 1 requires 5'-phosphate, 3'-hydroxyl, and free 2'-hydroxyl; substrate incompatible with 2'-OMe at ligation junction in wild-type form

notes: Primary mechanistic constraint paper for T4 Rnl1; key for explaining why engineered ligases are required for 2'-modified siRNA ligation; also used in Ch07 for T4 PNK requirement in ligation workflows


title: Codexis signs agreement to manufacture 50 g siRNA using its ECO Synthesis® Manufacturing Platform

venue: Codexis IR Press Release

key_claim: Codexis agreed in March 2026 to manufacture 50 g siRNA for a cardiovascular indication preclinical program via ECO Synthesis; confirms commercial traction

conflict_of_interest: Company press release; fact of agreement independently verifiable from IR filing

notes: March 4, 2026 announcement; confirms ECO Synthesis is at commercial engagement stage


title: GreenLight Announces Completion of Merger with Fall Line Endurance Fund — $45.5M go-private transaction, July 24, 2023

venue: GlobeNewswire / Goodwin Law

key_claim: GreenLight Biosciences Holdings taken private July 24, 2023 at $45.5M; surviving entity pivoted exclusively to agriculture RNA (Calantha, Norroa); therapeutic siRNA program discontinued

conflict_of_interest: None — factual M&A announcement

notes: CRITICAL CORRECTION: GreenLight did NOT go bankrupt; it was acquired and pivoted to agriculture. The $1/g IVT cost claim applies to agricultural unmodified dsRNA only, not therapeutic siRNA


title: Revolutionizing Nucleic Acid Synthesis with Engineered Enzymes — Codexis TIDES EU 2023 Presentation (TdT engineering)

venue: Codexis / TIDES Europe Conference

key_claim: Iterative TdT evolution showing progressive improvement in 2'-OMe and 2'-F modified NQP incorporation efficiency across multiple evolution rounds

conflict_of_interest: Company presentation; data appears genuine process development disclosure

notes: 2023 TIDES EU presentation; shows TdT engineering in progress for modified RNA; current status (2025-2026) per DeciBio Q&A suggests still not at GMP-ready stage for full alternating 2'-OMe/2'-F 21-mers


title: Nuclease P1 Digestion for Bottom-Up RNA Sequencing of Modified siRNA Therapeutics

authors: Jones JD et al.

venue: Analytical Chemistry (ACS)

key_claim: Nuclease P1 provides robust bottom-up siRNA sequencing regardless of 2'-fluorination, phosphorothioate content, 2'-OMe substitution, sequence, or length; outperforms RNase T1 for heavily modified siRNAs

conflict_of_interest: None disclosed; US government funded (non-PHS)

notes: Six digestion schemes tested systematically; nuclease P1 partial digest identified as primary method for 2'-modified siRNA; directly relevant to dual-target siRNA QC characterization workflow


title: GMP-grade Products for Nucleic Acid Therapeutics Manufacturing — NEB brochure

authors: New England Biolabs

venue: NEB GMP Product Documentation

key_claim: NEB GMP-grade spec: purity ≥90% SDS-PAGE; endotoxin ≤5 EU/mL; AOF; ISO 9001+ISO 13485; cross-contamination panels for residual exo/endonuclease; 43,000 sq ft Rowley MA facility opened 2018

conflict_of_interest: Company self-description; specifications are independently verifiable via CoA requests

notes: Primary documentation for GMP enzyme specification requirements; facility opening date confirmed from NEB public communications


title: Ribonuclease T1 — Worthington Biochemical product page

authors: Worthington Biochemical Corporation

venue: Worthington Biochemical

key_claim: RNase T1 from Aspergillus oryzae; 11 kDa; cleaves 3' of guanosine 3'-phosphate residues forming intermediate 2',3'-cyclic phosphates; fraction of global RNase market volume

conflict_of_interest: Commercial vendor; product description; enzyme properties are independently established in primary literature

notes: Supplier position context only; used for RNase T1 biochemical property confirmation; not primary literature; score below threshold for sole-source claims


title: Industry Insights: Advances in enzymatic manufacturing, therapeutic pipelines, and regulatory pathways for nucleic acid therapeutics

authors: Nucleic Acid Insights editorial

venue: Nucleic Acid Insights 2026;3(1)

key_claim: Alnylam USD 250M investment in siRELIS enzymatic ligation platform at Norton MA facility (December 2025); Codexis-Nitto ECO Synthesis evaluation agreement (October 2025)

conflict_of_interest: Trade journal; independently corroborates company press releases

notes: Confirms enzymatic ligation platforms at commercial/pre-commercial scale; Alnylam investment corroborated by BioPharm International Oct 2025 article


title: Yeasen GMP Grade mRNA Enzymes and Nucleotides for vaccine and drug development

authors: Yeasen Biotech

venue: Yeasen Biotech Technical Blog

key_claim: Yeasen is first Chinese company with ISO 13485 for molecular enzyme manufacturing; mRNAtools facility 50,000 sq ft; >5B units/yr capacity; FDA DMF numbers held for multiple products; GMP portfolio: T7 RNAP, DNase I, RNase inhibitor, BspQI

conflict_of_interest: Company-authored technical marketing; ISO 13485 certification and DMF facts independently verifiable from regulatory databases

notes: Primary evidence for Chinese domestic substitution status; ISO 13485 claim is verifiable; catalog review confirms no GMP nuclease P1 or RNase T1 for oligo-QC applications as of April 2026


title: Vazyme product catalog — DNase I RNase-free and RNase Inhibitor GMP-grade product listings

authors: Vazyme International (688105.SH)

venue: Vazyme Global website

key_claim: Vazyme offers DNase I RNase-free and Murine RNase Inhibitor GMP-grade; no GMP-grade nuclease P1, RNase T1, SVPD, or T4 PNK for oligonucleotide applications in current catalog

conflict_of_interest: Commercial vendor catalog; catalog completeness cannot be guaranteed without direct inquiry

notes: Used to establish the gap in Chinese domestic GMP supply for siRNA-specific QC enzymes; catalog-based inference; direct vendor inquiry recommended for confirmation


title: In-Depth Impurity Assessment of Synthetic Oligonucleotides Enabled by HRMS — CDER/OPQ/OTR SBIA 2022 Presentation

authors: Kui Yang, FDA/CDER Division of Complex Drug Analysis

venue: FDA CDER SBIA 2022 Conference

key_claim: FDA CDER explicitly states no ICH or general CMC guidance exists for synthetic oligonucleotides; HRMS isobaric resolution of n-U vs n-C (0.004 Da) is operative review standard; first PSG (nusinersen) issued Feb 2022

conflict_of_interest: Official FDA CDER presentation — no conflict

notes: Tier 1 regulatory source; direct FDA statement on guidance gap; HRMS methodology presented as internal standard; confirms PSG timeline; score 8.5 (authority 3.0 + recency 1.5 [2022] + primacy 2.0 + verifiability 2.0 + coi 1.0 = 9.5 → adjusted to 8.5 for 2022 date)


title: ICH Q3D(R2) Elemental Impurities — Guideline for Industry (Step 4, April 2022)

authors: ICH Quality Expert Working Group

key_claim: Cu parenteral PDE = 300 µg/day; Cu oral PDE = 3,000 µg/day; Cu inhalation PDE = 30 µg/day (Table A.2.1); Cu is Class 3; intermittent dosing subfactor justification available per §3.3

conflict_of_interest: None — official international regulatory guideline

notes: CRITICAL: Cu parenteral PDE = 300 µg/day, NOT 30 µg/day (30 is the inhalation PDE). Also available at FDA URL https://fda.gov/media/148474/download. Scores: authority 3.0 + recency 1.5 + primacy 2.0 + verifiability 2.0 + coi 1.0 = 9.5 → capped at 9.0 for practical maximum


title: ICH Q13 Continuous Manufacturing of Drug Substances and Drug Products — Step 4 Final Guideline

venue: ICH

key_claim: Adopted Nov 16, 2022; covers CM of chemical entities and therapeutic proteins; principles 'may also apply to other biological/biotechnological entities'; requires batch definition, material diversion, disturbance detection for CM processes

conflict_of_interest: None — official ICH guideline adopted by FDA, EMA, PMDA

notes: Step 4 document adopted by all ICH regions; FDA implementation guidance published Feb 2023; enzymatic ligation flow reactors fall within conceptual scope of CM definition


title: CDE Opens 3 Draft Guideline Consultations: Oligonucleotides, Advanced Therapies, and Biologics

authors: Reuben McClymont, Cisema

venue: Cisema Regulatory Intelligence

key_claim: CDE draft consultation for oligonucleotide guidance opened Sep 8, closed Oct 8, 2025; 4-category impurity framework (I–IV) with 1.5% qualification threshold; final guidance issued Feb 24, 2026

conflict_of_interest: Regulatory consultancy (Cisema); commercial interest in accurate regulatory intelligence for clients; no direct product conflict

notes: Cisema is a specialized China regulatory consultancy (20+ years, 100+ specialists); accurately describes draft timeline and impurity framework; corroborated by CDE Notice No. 21/2026 official document


title: Draft Guideline on the Development and Manufacture of Oligonucleotides (EMA/CHMP/CVMP/QWP/262313/2024)

authors: EMA CHMP/CVMP Quality Working Party

venue: European Medicines Agency

key_claim: §4.2.2: ICH Q13 requirements apply when continuous manufacturing is intended for oligonucleotides; §4.3.2: 4-class impurity framework (Class I–IV), 1.0% identification / 1.5% qualification thresholds; §4.2.3: phosphoramidites acceptable starting materials with justification per ICH Q11

conflict_of_interest: None — official EMA scientific guideline (draft)

notes: Draft; consultation closed Jan 31, 2025; not yet finalized as of April 2026 — cited as draft, not final. Tier 1 for authority even as draft; 27 pages; §4.2.2 explicitly references Q13; §4.3.2 impurity framework nearly identical to NMPA final version — strong cross-validation


title: Nonclinical Safety Assessment of Oligonucleotide-Based Therapeutics — Draft Guidance for Industry (FDA/CDER, November 2024)

authors: FDA/CDER Office of New Drugs

venue: FDA CDER

key_claim: All elements of ONT drug product must be assessed for off-target hybridization including 'both the sense and antisense strands, overlapping ends'; dual-strand characterization required in nonclinical program

conflict_of_interest: Official FDA CDER draft guidance; no conflict

notes: Draft guidance (60-day comment period from Nov 2024); when finalized will be operative standard; dual-strand assessment requirement directly informs CMC strand-level specification expectations; AAM docket comment Jan 2025 requests ANDA pathway guidance for oligonucleotides — harmonization unresolved


title: Learning from the Letters: FDA Complete Response Letter Trends 2020–2024 and What They Mean for Sponsors

authors: Devin Sears, Auria Compliance Group

venue: Auria Compliance Group Blog

key_claim: 74% of 202 FDA CRLs issued 2020–2024 cited CMC/manufacturing deficiencies; CMC failures are leading approval bottleneck across all drug classes

conflict_of_interest: Regulatory consultancy; commercial interest in accurate FDA trend analysis for clients; no direct product conflict

notes: Based on 202 redacted CRLs FDA released July 2025; large dataset; 74% figure corroborated by PharmTech March 2026 article citing same data release; Tier 2 (regulatory consultancy analysis of primary regulatory documents)