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Gene Therapy Medicinal Products

Gene Therapy Medicinal Products (GTMPs) can be broadly classified based on the approach to delivery and include the following :

  • Naked DNA (Non viral vectors) : natural or synthesized nucleic acids, generally ligated into appropriate plasmids or cassettes, in a simple formulation with or without adjuvant.
  • Complexed plasmids (Non viral vectors) : nucleic acids complexed with polycations, polymers or encapsulated / associated with liposomes or even, coated on colloidal particles that enhance their ability to penetrate the cell.
  • Viral vectors : viruses that harbor the gene(s) of interest but usually without the mechanism to self-replicate in vivo.

Thanks to over 30 years’ experience in analytical sciences and all our laboratories (Mass Spectrometry, Physico-chemistry, Cell Biology, Molecular Biology and Microbiology) on one site, Quality Assistance covers a wide range of analytical technologies needed to support your drug development process including product characterisation, development and validation of analytical methods, stability studies, batch testing and bioanalysis to support PK/TK, biomarker and immunogenicity studies.

Our capabilities in this area are summarized in the following table :

MCB/MVB & WCB/WVB
Identity of cells by phenotypic/genotypic markers RT-PCR / Q-PCR
Presence and integrity of vector Restriction endonuclease mapping
Measurement of vector gene expression Cf. potency
General Quality
Appearance Visual inspection
pH  
Osmolarity  
Extractable volume  
Residual moisture (if lyophilised)

KF titration

Identity
Cross-contamination with other products Restriction digest / Gel electrophoresis
Transgene expression Immunoassays / SDS-PAGE / RT-PCR
Transcription unit DNA confirmation Restriction enzyme mapping / PCR
Complex identity (proteins, lipids, polymers) Peptide Mapping (UPLC (UV, QTOF, IonTrap), MALDI-TOF) / GC (MS) / IEX / RID
Plasmid, DNA identity Restriction enzyme mapping / PCR
DNA homogeneity Electrophoresis (agarose) / Bioanalyzer / CE
Genomic structural integrity PCR
Plasmid-selection markers PCR / To be discussed
Purity & Integrity
Plasmid DNA conformation (monomeric supercoiled, relaxed monomer, linear, ccc [circular covalently closed] vs oc [open circular] ) Electrophoresis (agarose), CE
Optical density ratio (A260/A280) Spectrophotometer
Viral protein profile (defective or immature particles) (U)HPLC (UV, MS)
Structural protein analysis (U)HPLC (UV, MS) / SDS-PAGE / Peptide Mapping (UPLC (UV, QTOF, IonTrap), MALDI-TOF)
Complex purity (proteins, lipids, polymers) Peptide Mapping (UPLC (UV, QTOF, IonTrap), MALDI-TOF) / GC (MS) / IEX
Ratio gene/vector and stability (U)HPLC (UV)
(Viral-) vector purity (U)HPLC (UV) / Spectrophotometer
Viral capsid purity SDS-PAGE
Homogeneity of size Electrophoresis (agarose)
Dose
Viral particle number, concentration (U)HPLC (UV) / IEX (UV) / UV
Total protein Micro BCA
Formulated-complex weight (U)HPLC (UV) / CE
Gene-vector titer, infectious titer Bioassays / Q-PCR
Plasmid DNA weight, DNA titer UV / PicoGreen / Q-PCR
Viral DNA copies Q-PCR
Ratio particle concentration / infectious titer A4F/HF5 (UV, RI, MALS)
Vector copy number ELISA / Q-PCR
Potency
Labeled dose UV / Q-PCR
Function of expressed gene Cell-based assays
Infection, transfection/transduction Cell-based assays / Q-PCR
Transgene expression after transfection in cells Cell-based assays / Western Blot / ELISA / RT-PCR
In Vitro viral genome copy number in cells Q-PCR
Product-related Impurities
Defective, immature and empty viral particles A4F/HF5 (UV, RI, MALS)
Single strand DNA Threshold
Vector aggregates A4F/HF5 (UV, RI, MALS) / DLS
Transgene product Cf. Product sheet «Proteins»
Process-related Impurities
Residual DNA (bacterial chromosomal DNA, genomic DNA, plasmid DNA, HCDNA) Q-PCR
Residual RNA Ribogreen / Electrophoresis (agarose)
Residual proteins (HCP, bacterial proteins) (SDS-)PAGE / Western Blot / ELISA / ECL (MSD)
Medium components (FBS, antibiotics, cytokines, hormones, BSA, enzymes, antibodies, growth factors) ELISA / ECL (MSD) / (U)HPLC (UV, FLUO, MS) / Luminex
Process contaminants (serum, CsCl, EtBr, Iodixanol, alakaline detergents, acetate, PEG) CE / GC (MS) / (U)HPLC (MS) / ELISA / ICP (MS)
Residual benzonase ELISA
Residual solvents HS-GC (FID, MS) / (U)HPLC (UV)
Residual salts (U)HPLC (conductimetry, amperometry) / IEX (conductimetry) / ICP (OES, MS)
Heavy metals / Elemental impurities ICP (OES, MS)
Microbiology / Endotoxins Bioburden / Sterility (filtration, direct inoculation) / Endotoxins (kinetic, end point)
Packaging
Container closure system integrity Bubbling / Dye ingress  / Microbial ingress
Leachables and extractables GC (FID, ECD, MS) / ICP (OES, MS) / (U)HPLC (UV, ELSD, CAD, MS)
Cytotoxicity / Biological reactivity Cell-based assays / USP <87>
Immunogenicity & PK/TK & Biomakers
Immunogenicity (on transgene product) ELISA / ECL (MSD) / Cell-based assays (neutralization) / Luminex / Biacore
PK/TK Q-PCR / ELISA / ECL (MSD) / Luminex / Biacore
Biomarkers ELISA / ECL (MSD) / UPLC (MS/MS) / Luminex
Vehicles / Buffers Q-PCR / UV / (U)HPLC (UV, RI, DAD, FLUO, ELSD, CAD) / ICP (OES, MS)

 

You can download the full table of GTMP analysis here!

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