Pharmadite® for Pharmaceutical Applications

Standard Phosphoramidites   DNA and RNA Pharmadite®   DNA Phosphoramidite   2'O-TC RNA Phosphoramidite   2'O-TBDMS RNA Phosphoramidite   2'O-Methyl Phosphoramidite   2'Fluoro Phosphoramidite   5'-NPPOC DNA Phosphoramidite   Non-Standard Nucleosides Phosphoramidite Fast Deprotection Chemistry (FD)   FD DNA Phosphoramidite   2'O-TBDMS RNA Phosphoramidite

Supports   Bulk Controlled Pore Glass (CPG)  DNA CPG  RNA CPG  Amino-ON CPG  Universal CPG Columns   DNA CPG Column   RNA CPG Column   DNA Polystyrene Column

Labels and Modifications   6-FAM   Fluorescein Phosphoramidite   Biotin Phosphoramidite   Phosphate-ON Linkers   MMT and TFA Amino Linker   ssH Linker Solvents   Liquid Reagents   Activator 42®

The Pharmadite product line represents a new class of standard protected DNA and RNA phosphoramidites designed with highly controlled impurity profiles and exceptional overall purity. Pharmadite products fulfill all the requirements of starting materials for the manufacture of active pharmaceutical ingredients as defined in the EMEA 'Note for guidance on chemistry of the new active substance'*, making them suitable building blocks for oligonucleotide drugs.             Download Literature:   •  Pharmadite Flyer (217k pdf)   View Structure:   •  DMT-dA(bz) Pharmadite   •  DMT-dC(bz) Pharmadite   •  DMT-dG(ib) Pharmadite   •  DMT-dT Pharmadite Pharmadite amidites are manufactured in scales of up to multi-hundred kilos, under certified ISO 9001 quality systems at SAFC Supply Solutions manufacturing facility in Hamburg, Germany. We start with traceable, non-animal and very pure raw materials, use highly controlled synthesis and purification processes, validated analytical methods and cleaning processes, all governed with strict change control and documentation to yield unprecedented high quality products with purity ratings at 99.5% or higher for DNA and 99.0% or higher for RNA. All remaining impurities, if present, are identified and characterized at a level of 0.1%. The high level of control and documentation imposed at every step of the production process support regulatory requirements to make Pharmadite amidites ideal for pharmaceutical applications. Key Features of Pharmadite Benefits Consistent quality Reproducible oligonucleotide synthesis Suitability as starting material for API manufacture Accordance with regulatory guidelines   - Raw material control and traceability       - Process control       - Validated analytical methods       - Tight specifications       - Known impurity profiles     Very high purity High production efficiency Non-animal origin of starting materials TSE safety Available in large scale Secure supply Supply through our worldwide supply chain Long-term reliability Manufacturing Pharmadite amidites are prepared from DMT-protected nucleosides and the phosphitylating agent "bis-amidite." To ensure the highest quality our production process begins with starting materials that possess stringent specifications and defined impurity profiles. The crude phosphoramidites are then purified by preparative HPLC, dried and packaged. Our HPLC production line is cleaned using validated cleaning methods and cleaning verification is performed prior to each batch. Reactions are conducted at a minimum synthesis scale of 50 kg per batch. Each processing step is monitored using analytical in-process controls, including HPLC. Specifications Pharmadite amidites are characterized by their exceptional purity and well-defined impurity profile. In particular, they are essentially free from contaminants which interfere in coupling reactions, such as other nucleosidic or non-nucleosidic phosphoramidites (P(III)-contaminants). DNA Pharmadites Characteristics Acceptance Limit Appearance white to off white powder or granules Appearance of Solution ≤ 10 Hazen (c = 0.2M in ACN) Solubility clear solution (c = 0.2M in ACN) HPLC Identification conforms HPLC Purity ≥ 99.5 % area Single Specified Impurity (see impurities table for referece below) Single Unspecified Impurity ≤ 0.1 % area 31P NMR Purity ≥ 99.5 % area 31P NMR P(III) Impurities (@ 100 to 169 ppm) ≤ 0.1 % area 31P NMR P(V) Impurities (@ -25 to 99 ppm) ≤ 0.5 % area 31P NMR ≥170 ppm Impurities (@ 170 to 225 ppm) not detected: S/N < 2.5 Residual Solvent Content ≤ 3.0 % wt Water Content ≤ 0.40 % wt Origin of Nucleoside non animal origin RNA Pharmadites Characteristics Acceptance Limit Appearance white to off white powder or granules Appearance of Solution ≤ 10 Hazen (c = 0.2M in ACN) Solubility clear solution (c = 0.2M in ACN) HPLC Identification conforms HPLC Purity ≥ 99.0 % area Single Specified Impurity (see impurities table for referece below) Single Unspecified Impurity ≤ 0.1 % area 31P NMR Purity ≥ 99.0 % area 31P NMR P(III) Impurities (@ 100 to 169 ppm) ≤ 0.3 % area 31P NMR P(V) Impurities (@ -25 to 99 ppm) ≤ 1.0 % area 31P NMR ≥170 ppm Impurities (@ 170 to 225 ppm) not detected Residual Solvent Content ≤ 3.0 (w/w) Water Content ≤ 0.40 (w/w) Origin of Nucleoside non-animal origin All remaining impurities in Pharmadite amidites, if present, are identified, characterized and quantified. The impact of any such defined impurities on the synthesis of oligonucleotides is well understood and has been shown to be insignificant. Specified Impurities of DNA Pharmadites A C G  T  DMT-dNucleoside-cyanoethyl-H-phosphonate ≤ 0.3% ≤ 0.3% ≤ 0.3% ≤ 0.3% DMT-dNucleoside phosphoramidate ≤ 0.3% ≤ 0.3% ≤ 0.3% ≤ 0.3% DMT-dNucleoside-diisopropylamino-H-phosphonate not specified not specified ≤ 0.3% not specified 03'-Benzoyl-O5'-DMT-dC(bz) not applicable ≤ 0.3% not applicable not applicable Specified Impurities of RNA Pharmadites A C G  T  2'O-Amidite-3'O-TBDMS-5'O-DMT-rNucleoside ≤ 0.3% ≤ 0.3% ≤ 0.3% ≤ 0.3% DMT-rNucleoside TBDMS ≤ 1.0% ≤ 1.0% ≤ 1.0% ≤ 1.0% DMT-rNucleoside TBDMS-cyanoethyl-H-phosphonate ≤ 1.0% ≤ 1.0% ≤ 1.0% ≤ 1.0% DMT-rNucleoside TBDMS-phosphoramidate ≤ 1.0% ≤ 1.0% ≤ 1.0% ≤ 1.0% Quality system and production process designed to meet pharmaceutical standards. Control of starting materials and production process is a key factor in the synthesis procedure of RNA Pharmadite. The phosphitylating reagent is controlled at a level of 0.1% P(III)- impurities. RNA Pharmadite amidites are purified by preparative HPLC in a highly automated purification plant. Having been ISO 9001 certified since 1993, Proligo Reagents' production facility in Hamburg, Germany (GE) guarantees a reproducible quality, a predictable and controlled production: Robust process parameters In-process controls with specifications Batch integrity Change control Batch record review Process database and trend analysis Validated cleaning procedures DNA Pharmadites Product No. Description A111P00-C DMT-dA(bz) Pharmadite C111P00-C DMT-dC(bz) Pharmadite G111P00-C DMT-dG(ib) Pharmadite T111P00-C DMT-dT Pharmadite RNA Pharmadites A211P00-C DMT-2'O-TBDMS-rA(bz) Pharmadite C213P00-C DMT-2'O-TBDMS-rC(ac) Pharmadite G211P00-C DMT-2'O-TBDMS-rG(ib) Pharmadite U211P00-C DMT-2'O-TBDMS-rU Pharmadite *EMEA: European Medicines Agency, www.emea.eu.int

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