D1S11-Liang-1.2-FINAL.pdf

1、Quality Considerations for Generic Oligonucleotides Likan Liang,Ph.D.Division of Product Quality Assessment XOffice of Product Quality Assessment II,OPQ,CDER Generic Drugs Forum 2026FDA White Oak Campus,Silver Spring,MarylandApril 22-23,20262Pharmaceutical quality assures the availability,safety,and

2、 efficacy of every dose.Everyone deserves confidence in their next dose of medicine.www.fda.gov3www.fda.govDisclaimerThis presentation reflects the view of the author and should not be construed to represent FDAs views or policies.The mention of trade names,commercial products,or organizations is fo

3、r clarification of the information presented and should not be interpreted as an endorsement of a product or manufacturer.The author declares no competing financial interest.4www.fda.govOligonucleotide(ON)Drug ProductsShort strings of synthetic or semisynthetic nucleic acids with therapeutic effects

4、Nucleic acid structuresUnmodified(e.g.,Defibrotide)Modified(most CDER-approved ONs)Single stranded(e.g.,ASO),double stranded(e.g.,siRNA),etc.5www.fda.govON Modifications and Diastereomers2 modification(R=F,O-methyl,O-methoxyethyl,etc.)3 modificationBase modification(e.g.,methyl-cytosine)5-end conjug

5、ation(e.g.,PEG,fatty acid)2 conjugation (e.g.,N-acetylgalactosamine (GalNAc)3-end conjugation(e.g.,GalNAc)Nucleotide linkage modification:(e.g.,non-stereospecific phosphorothioate(PS):R and S ratio each PS.n x PS:PS diastereomers=2nComplexity of ON Stereochemistry!6www.fda.govNucleotide linkage modi

6、fication:(e.g.,non-stereospecific phosphorodiamidate(PDA):R and S ratio each PDAn x PDA:PDA diastereomers=2nComplexity of ON Stereochemistry!ON Modifications and Diastereomers(cont.)7Diastereomers in CDER-Approved Oligonucleotide Drug ProductsType of ONCDER-Approved ONs aLength of ONs cModifications