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  • CMC Pharmaceutical D l t S iDevelopment Services

    CONFIDENTIAL 2015 China Gateway Pharmaceutical Development

  • Pharmaceutical Development: A New FacilityPharmaceutical Development: A New Facility

    A Pharmaceutical Development Center Fengxian, Shanghai Designed by Foster Wheeler U


    WT Designed by Foster-Wheeler cGMP compliant

    Facility Pilot Plant 5251 m2





    Pilot Plant 5251 m(including cyrogenic and hydrogenation/pressure)

    Kilo-Lab 5260 m2 Admin / R&D Lab 14690 m2 Utilit B ildi 2823 2 Utility Building 2823 m2 Warehouse 3480 m2 Flammable/Cold 748 m2 Waste Water Treatment 1100 m2

    T l 18893 2*

    Total: 18893 m2

    Equipment Installation and Qualification

    Kilo-Labs and Pilot Plant fully GMP *


    operational September, 2011


  • Pharmaceutical Development: Overview

    Strategy Provide full pharmaceutical development servicesFocus on early phase development from NCE selection to FIH to Phase IIa


    Senior management team with average of >13 years of global pharmaceutical experience

    85 chemical development chemists70 analytical and formulation scientists


    120 engineers, operators and supporting staff

    Over 260 international and domestic Pharmaceutical, biotechnology, virtual, fine chemical

    Chemical Development & Manufacturing cGMP Kilo-Lab Suites / Process R&D labs cGMP Pilot Plant with 48 reactors (5 6,300 L)

    Facilities Analytical Development 19,055 ft2 (1920 m2) lab/office space*

    Formulation Development 7,000 ft2 (800 m2) lab/office space*


    Business Model FTE / FFS / Production Management


  • Pharmaceutical Development: Process Development

    FFS/FTE Projects Over 675 CMC Development projects completed to date Projects ranging from R&D to full scale manufacturing of >3 MT of advanced intermediates Completed 25 cGMP campaigns to date to meet customer needs for clinical grade API, including 12

    International based customers (US, Europe, Japan and Taiwan)

    Process Research, Development, and Optimization Process development of discovery routes into robust manufacturing processes suitable for intended purpose Process development of discovery routes into robust manufacturing processes suitable for intended purpose

    Replacement of column chromatography with precipitation/crystallization Implement appropriate, robust IPCs for reaction,

    determining ratio of solvents for any solvent swaps and completion of drying Replacement of use of drying agents with azeotropic drying Avoid concentration to a residue Target fit-for-purpose volumetric efficiency Avoid use of non-Pilot Plant friendly solvents/reagentso d use o o o a e d y so e s/ eage s Avoid use of expensive reagents Identify appropriate ranges for key processing parameters, including stress testing of the reaction, work-

    up, isolation and drying conditions to develop a fit-for-purpose manufacturing route Determine appropriate fit-for-purpose acceptance criteria for key starting materials and intermediates


    Determine appropriate fit for purpose acceptance criteria for key starting materials and intermediates


  • Pharmaceutical Development: Process Development

    Process Research, Development, and Optimization (Continued) Route scouting / selection for new scalable processes, including generation of innovative solutions to complex

    synthetic problems Critical process parameter evaluation / justification Technology transfer to manufacturing production Safety evaluation / hazard assessment, including calorimetry

    R h d D l t M f t i Research and Development Manufacturing Advanced Intermediates, Registration Starting Materials and APIs Process development support for commercialization Up to metric tonne scale

    Custom Synthesis Drug discovery & Preclinical development support

    Impurity markersC t Comparators

    CMC CTD Support Registration Starting Material Strategy Impurity management fate and linkage


    Impurity management fate and linkage Potential Genotoxic Impurity Management


  • Pharmaceutical Development: Manufacturing Facility

    Filter Dryer

    CONFIDENTIAL2015ChinaGatewayPharmaceuticalDevelopment 6

    Filter Dryer

  • Pharmaceutical Development: Pilot Plant Overview

    Total Area: 5251 m2

    Building Height: 18 m with 3 levels

    9 Individual Processing Bays, Including 4 Special Bays and 2 Clean Rooms (Class 100,000)

    48 Reactors (5 to 6,300 L, total 72 m)

    DCS Control, 1 Bay with Recipe Control

    Reaction Temperature: -80 to 300

    Reaction Pressure: -0. 1Pa to 10MPa (95 Atm)

    CONFIDENTIAL2015ChinaGatewayPharmaceuticalDevelopment 7

  • Pharmaceutical Development: A New Facility Bay 4

    R-0341 1000 L SS R-0342 1000 L GL

    R 0343 500 L GL R-0343 500 L GL R-0344 500 L GL F-0341 DN 600 Halar Coated

    (10 kg/load) D-0341 300 L Titanium

    (24 Trays)

    CONFIDENTIAL2015ChinaGatewayPharmaceuticalDevelopment 8

  • Pharmaceutical Development: A New Facility Bay 6

    R 0361 1000 L GL 3rd FloorDCS Recipe Control

    R-0361 1000 L GL 3rd Floor R-0362 1000 L GL 3rd Floor R-0363 1000 L GL 3rd Floor R-0356 6300 L GL 2nd Floor R-0364 3000 L GL 2nd Floor

    R 0365 3000 L GL 2 d Fl R-0365 3000 L GL 2nd Floor R-0366 1000 L GL 2nd Floor F-0361 DN800 Halar Coated

    (30 kg/load) D-0361 500 L SS Twin Cone

    CONFIDENTIAL2015ChinaGatewayPharmaceuticalDevelopment 9

  • Pharmaceutical Development: A New Facility Bay 9

    Cryogenics: -80C to 80C

    R-0383 300 L SS

    y g

    R-0384 500 L SS R-0385 2000 L SS R 0386 5000 L SS R-0386 5000 L SS Liquid Nitrogen Cooling Cryogenic TCU Control

    CONFIDENTIAL2015ChinaGatewayPharmaceuticalDevelopment 10

  • Pharmaceutical Development: A New Facility Bay 9

    Pressure Bay

    R-0373 5 L SS

    (For Pressure Reactions including hydrogenation & carbonylation)

    R 0373 5 L SS (to 350C, 95 Atm)

    R-0372 50 L SS(t 350C 95 At )(to 350C, 95 Atm)

    R-0371 500 L Hastelloy C276 (to 180C, 76 Atm)

    R-0376 3000 L Hastelloy C276(to 140C, 57 Atm)

    CONFIDENTIAL2015ChinaGatewayPharmaceuticalDevelopment 11

  • Pharmaceutical Development: A New Facility Clean Room 2 Finishing Area

    Class 100,000 : 100 Kg Batch Size

    R-0368 1000 L GL (Crystallizer)

    R 0369 500 L GL (C t lli )


    R-0369 500 L GL (Crystallizer)

    F-0362 DN600 SS Horizontal


    D-0362 500 L Titanium Twin Cone

    Jet mill 3 to 5 Kg/Hour

    CONFIDENTIAL2015ChinaGatewayPharmaceuticalDevelopment 12

  • Pharmaceutical Development: A New Facility GMP Kilo-Lab Suites

    Each Kilo-Lab Suite Equipped with:100 L Gl Li d R t 2 100 L Glass Lined Reactors: 2

    50 L Glass Jacketed Reactor(ChemGlass): 3(ChemGlass): 3

    TCU Control Centrifuge DN300: 2 Vacuum Tray Dryer, 5 Kg/Batch: 2

    Clean Room 3 Class 100,000 5 Kg Batch Size

    CONFIDENTIAL2015ChinaGatewayPharmaceuticalDevelopment 13

  • Pharmaceutical Development: Typical Projects

    Project Code Client LocationProject

    DescriptionType of

    Compound Total

    AmountNumber Steps Comment

    CG428 USA API 30 kg 3 GMP for Phase I/II clinical trials, chiral epoxide openingchiral epoxide opening

    CG467 USA API 2 Kg 2 GMP for Phase I clinical trials,acid chloride coupling

    CG510 USA API 30 Kg 5 GMP for Phase I clinical trials, Pd couplingPd coupling

    CG502 USA/China API 2 x 50 Kg 9GMP for Phase I/II clinical trials, Pd coupling and hydrogenation

    CG498 E API 10 K 8 GMP Chiral SFC separation forCG498 Europe API 10 Kg 8 GMP Chiral SFC separation for an advanced intermediate

    CG319 USA API 3.5 Kg 14

    GLP Tox Study,Enzyme resolution/ 78C Simmons Smith-78C Simmons-Smith Cyclopropanation

    CG427 USA API 3 Kg 14GLP Tox Study,

    Suzuki coupling, Chiral CBS reduction

    CONFIDENTIAL2015ChinaGatewayPharmaceuticalDevelopment 14


  • Pharmaceutical Development: Typical Projects Cli t P j t T f T t l N bProject Code Client Location

    Project Description

    Type of Compound

    Total Amount

    Number Steps Comment

    CG480Europe Nitro Aromatic

    RSM 3400 Kg 1Alkylation, Included in

    Registration Dossier for a marketed productmarketed product

    CG459 USA Chloroquinol RSM 150 kg 6 Nitration, hydrogenation

    CG204 USA Aromatic RSM 350 Kg 9 Aromatic nitration, LDA mediated aromatic methylationmediated aromatic methylation

    CG371USA Isooxazole

    Advanced Intermediate

    1500 Kg 9 Ellman sulfinamide chiral chemistry

    CG397 USA P l li RSM 600 K 6 Low temperature couplingCG397 USA Polycylic RSM 600 Kg 6 Low temperature coupling reaction, intramolecular D-A

    CG383 EuropeAldehyde Advanced

    Intermediate150 Kg 5 Chromium oxidation, TEMPO bleach Oxidation

    CG448 USA Chiral amine RSM 200 Kg 6Chiral epoxide opening,

    morpholine formation

    CG400 USA Long chain diacid 2 x 250 Kg 3Olefin metathesis reaction, high temp green hydrolysis

    ( oC)

    CONFIDENTIAL2015ChinaGatewayPharmaceuticalDevelopment 15

    diacid (>230oC)

  • Pharmaceutical Development: Typical Projects

    Project Code Client LocationProject

    DescriptionType of


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