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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
S
WT Designed by Foster-Wheeler cGMP compliant
Facility Pilot Plant 5251 m2
PPR&D
U
KL
WT
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 *
CONFIDENTIAL© 2015 China Gateway Pharmaceutical Development
operational September, 2011
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Pharmaceutical Development: Overview
Strategy Provide full pharmaceutical development servicesFocus on early phase development from NCE selection to FIH to Phase IIa
People
Senior management team with average of >13 years of global pharmaceutical experience
85 chemical development chemists70 analytical and formulation scientists
Customers
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*
CONFIDENTIAL© 2015 China Gateway Pharmaceutical Development
Business Model FTE / FFS / Production Management
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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
CONFIDENTIAL© 2015 China Gateway Pharmaceutical Development
Determine appropriate fit for purpose acceptance criteria for key starting materials and intermediates
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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
CONFIDENTIAL© 2015 China Gateway Pharmaceutical Development
Impurity management – fate and linkage Potential Genotoxic Impurity Management
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Pharmaceutical Development: Manufacturing Facility
Filter Dryer
CONFIDENTIAL© 2015 China Gateway Pharmaceutical Development 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 m³)
DCS Control, 1 Bay with Recipe Control
Reaction Temperature: -80 to 300
Reaction Pressure: -0. 1Pa to 10MPa (95 Atm)
CONFIDENTIAL© 2015 China Gateway Pharmaceutical Development 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)
CONFIDENTIAL© 2015 China Gateway Pharmaceutical Development 8
Pharmaceutical Development: A New Facility – Bay 6
• R 0361 1000 L GL 3rd Floor
DCS 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
CONFIDENTIAL© 2015 China Gateway Pharmaceutical Development 9
Pharmaceutical Development: A New Facility – Bay 9
Cryogenics: -80ºC to 80ºC
• 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
CONFIDENTIAL© 2015 China Gateway Pharmaceutical Development 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 350ºC, 95 Atm)
• R-0372 50 L SS(t 350ºC 95 At )(to 350ºC, 95 Atm)
• R-0371 500 L Hastelloy C276 (to 180ºC, 76 Atm)
• R-0376 3000 L Hastelloy C276(to 140ºC, 57 Atm)
CONFIDENTIAL© 2015 China Gateway Pharmaceutical Development 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 )
g
R-0369 500 L GL (Crystallizer)
F-0362 DN600 SS Horizontal
Centrifuge
D-0362 500 L Titanium Twin Cone
Jet mill 3 to 5 Kg/Hour
CONFIDENTIAL© 2015 China Gateway Pharmaceutical Development 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
CONFIDENTIAL© 2015 China Gateway Pharmaceutical Development 13
Pharmaceutical Development: Typical Projects
Project Code Client Location
Project Description
Type of Compound
Total Amount
Number 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 9 GMP 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
CONFIDENTIAL© 2015 China Gateway Pharmaceutical Development 14
reduction
Pharmaceutical Development: Typical Projects Cli t P j t T f T t l N bProject Code Client
LocationProject
DescriptionType of
Compound Total
AmountNumber 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 6 Chiral epoxide opening,
morpholine formation
CG400 USA Long chain diacid 2 x 250 Kg 3
Olefin metathesis reaction, high temp green hydrolysis
( oC)
CONFIDENTIAL© 2015 China Gateway Pharmaceutical Development 15
diacid (>230oC)
Pharmaceutical Development: Typical Projects
Project Code Client Location
Project Description
Type of Compound
Total Amount
Number Steps Comment
CG372 USAAldehyde Advanced 500 Kg 5
Cryogenic o-lithiation. Peracetic oxidation, USA
Intermediateg ,
Cryogenic DIBAL reduction
CG426 Europe Boronic acidIntermediate 50 Kg 2 Cryogenic reaction using BuLi
CG419 USA Fluoro Sugar RSM 100 Kg 9 Low temperature Wittig;
fl i ti tiCG419 RSM 100 Kg 9 fluorination reaction
CG482 USA RSM 1200 Kg 2 Esterification and Iodination
CG418 USA Skin Care 600 Kg 8 Enzymatic resolution; CG418 Product 600 Kg 8 Dynamic Kinetic Resolution
CG432 USAAmine
Advanced Intermediate
22 Kg 2 SNAr
Hydrazine reduction peracidCG429 USA Cyano-
azaindole 34 Kg 5Hydrazine reduction, peracid
oxidation and TMSCN cyanation
CG456 USAChiral
Advanced 26 Kg 7 Dynamic Kinetic Resolution
CONFIDENTIAL© 2015 China Gateway Pharmaceutical Development 16
Intermediate
Pharmaceutical Development: Analytical Development FFS/FTE Projects Stand alone and support for Process Development and Plant
campaigns, including GMP campaigns
In Process Controls In-Process Controls Method development and testing
Residual solvent analysis
Moisture content testing (KF titrations)o stu e co te t test g ( t t at o s)
Compendial testing (HM, ROI)
Counter-ion (ion-chromatography and titration)
Assay Method Development Impurity Characterizations Structural identification
Isolation
Impurity profiling
Release Testing Starting materials
Intermediates
CONFIDENTIAL© 2015 China Gateway Pharmaceutical Development
Intermediates
Results of Analysis
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Pharmaceutical Development: Analytical Development
Method Development: Chromatographic: HPLC, GC Non-chromatographic: wet chemistry spectroscopic etc Non-chromatographic: wet chemistry, spectroscopic, etc.
High Throughput Analysis and Purification HPLC with various detection techniques (DAD/MS/ELSD/CAD) Mass-directed autopurification P HPLC TLC d fl h h t h Prep-HPLC, prep-TLC, and flash chromatography
Structural Characterizations Mass spectroscopy: LC/MS, GC/MS, LC/MS/MS NMR: 1H-, 13C-, 19F-, 31P-, NOESY, DEPT, HSBC, HMQC, etc. FT-IR, UV, elemental analysis, counter-ion analysis, etc.
Physical Characterizations Physicochemical constant: pKa, logP/logD, melting point, etc. XRPD, TGA, DSC, DVS, particle size, etc.
Chemical Characterizations and General Testing Purity, residual solvents, KF titration, Heavy metal, ROI, LOD, etc. HPLC, GC, LC/MS, GC/MS, titration, ion chromatography, atomic absorption HPLC/CLND HPLC/FLD
CONFIDENTIAL© 2015 China Gateway Pharmaceutical Development
HPLC/CLND, HPLC/FLD Impurity isolations and characterizations
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Pharmaceutical Development: Analytical Development
Assay MethodsDrug Substances
Method Development Specificity
Identification (NMR, MS, IR, HPLC retention)
Purity and impurities (HPLC, LC-MS)
Residual solvents (GC, GC-MS)
Enantiomeric purity (e e )
No background interference Selectivity of columns
Chromatographic method Stability indicating
Enantiomeric purity (e.e.)
Counter-ion (IC, titration)
Compendial testing (HM, ROI, LOD)
Moisture content (Karl Fisher titration)
Forced degradation Recovery
Chemical Characterizations Impurity identification( )
Drug Products Identifications
Potency/Label Claim
Impurity identification Impurity profiling pH profile Degradation products Degradation mechanism/pathway
Moisture content
Dissolution
Content uniformity
Degradation mechanism/pathway Excipient compatibility
Stability Degradation
Di l ti
CONFIDENTIAL© 2015 China Gateway Pharmaceutical Development
Dissolution
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Pharmaceutical Development: Analytical Development
Drug ChemistryForced DegradationForced Degradation
Solid state (heat, heat/HR, light)
Solution state (water, acid, base, 0.3% H2O2, light)
pH profile (pH 2 - 10)p p (p )
Formulation media (0.5% HPMC, PEG, 20% HPBCD, etc)
Up to 2 weeks
Characterizations
HPLC and orthogonal methods
Degradation products by LC-MS
Proposed structures
Degradation mechanism
Impurity profiles
CONFIDENTIAL© 2015 China Gateway Pharmaceutical Development 20
Pharmaceutical Development: Analytical Development
Stability Management
Drug substances and products
Clinical supplies
Protocol driven
Customer defined report format
Stability indicating HPLC method development
Chamber IQ/OQ and calibrations
Storage at: Long term Intermediate Accelerated
CZ I + II 25C/60%RH or30C/65%RH or30C/75%RH*
30C/65%RH or 30C/75%RH*
40C/75%RH
CZ III + IVa 30C/65%RH or 30C/75%RH*
- 40C/75%RH
CZ IVb 30C/75%RH - 40C/75%RH
Refrigerator 5C - 25C/60%RH
CONFIDENTIAL© 2015 China Gateway Pharmaceutical Development
Freezer - 20C - -
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Pharmaceutical Development: Analytical Development
Method Validation
Preliminary
Regulatory submissions (IND/IMPD, NDA/MAA)
Reference Standard Qualification Appearance (USP) ID (by HPLC and IR) pH (USP)Regulatory submissions (IND/IMPD, NDA/MAA)
Drug Product Development Support
Method development
Excipient compatibility
pH (USP) Assay (stability indicating method) Related Substances Residual Solvent (GC method) C t I (I Ch t h )Excipient compatibility
Formulation screening
Accelerated stability
Method Transfer
Counter Ion (Ion Chromatography) Heavy Metal (USP) Metals (GFAA) Residue on Ignition (USP) Method Transfer
Originating/receiving laboratory
Routine Sample Analysis
Identity confirmation
Water Content (KF) X-Ray Diffraction (XRD) NMR Single Crystal XRD Identity confirmation
Purity determination/verification
Conformational testing
Customer defined or in house developed methods
Single Crystal XRD Elemental Analysis High Resolution Mass Spectrum UV/Vis H i it (DVS)
CONFIDENTIAL© 2015 China Gateway Pharmaceutical Development
Customer defined or in-house developed methods Hygroscopicity (DVS) TGA/DSC
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Pharmaceutical Development: Analytical Development
Solid State Characterizations Crystallinity XRD Th l l i (TGA/DSC h t t i )
Solution State Characterizations
HPLC Methods XRD, Thermal analysis (TGA/DSC, hot-stage microscopy)
Particle Size Measurement
Morphology Polarized microscope
Evaluation Development
Solubility Profile Ambient pH (1 – 8) Polarized microscope
Size, shape, birefringent
Hygroscopicity Water sorption/desorption isotherm
p ( ) Simulated fluids Organic solvents
Effect of Additives in Aqueous Media Ionic strength Dynamic vapor sorption
Stability Accelerated study Crystallinity and forms
Ionic strength Buffers Surfactants Cyclodextrins in aqueous systems
y y
Milling Effect Microscope, DSC, XRD
Stability pH (1 – 8) for 24 h Degradations Stability enhancement strategies
CONFIDENTIAL© 2015 China Gateway Pharmaceutical Development 23
Pharmaceutical Development: Chiral Separations
Analytical Method Development
Reaction monitoring and e.e. determination
Fast/Automatic HPLC and SFC condition screening
Optical rotation and specific rotation determination
Enantiomers identification (HPLC/SFC)Enantiomers identification (HPLC/SFC)
Enantiomeric Separations
Supercritical fluid chromatograph
Preparative HPLC
Capability from mg to kg
Generally, > 80% recovery, 95 ee%Generally, 80% recovery, 95 ee%
Other Separations
Regioisomers
CONFIDENTIAL© 2015 China Gateway Pharmaceutical Development
Diastereomers
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Pharmaceutical Development: Pharmaceutical Sciences
Physical Characterization and Form Definition
Salt and polymorph screening
Solubility
Solution and solid state stability
pKa/Log D/Log P determination pKa/Log D/Log P determination
Physical Properties for Formulation Development
Flowability
Particle size and size distribution
Bulk and tap densities
Drug Discovery Support for Candidate Selections
Pharmaceutical profiling
Developability assessment
CONFIDENTIAL© 2015 China Gateway Pharmaceutical Development 25
Pharmaceutical Development: Pharmaceutical Sciences
Salt Screening
Commonly used pharmaceutical salts
Solubility
Polymorph Screening
Screening Evaporation anti-solvent cooling slurry Solubility
Aqueous media
Crystallinity Thermal analysis (TGA/DSC, hot-stage
microscopy)
Evaporation, anti-solvent, cooling, slurry Crystallization in single and binary solvents
Crystallinity XRD as primary toolmicroscopy)
XRD
Morphology Polarized microscope Size shape birefringent
Thermal analysis, if needed
Solubility Aqueous media
Size, shape, birefringent
Hygroscopicity Water sorption/desorption isotherm
Hydrate formation possibility
Selected Form Repeat at larger scale Crystallinity Morphologyy p y
Water slurry, 24 hours
Counter Ion Content Ion chromatography
p gy Hygroscopicity Stability
CONFIDENTIAL© 2015 China Gateway Pharmaceutical Development
Solubility HPLC
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Pharmaceutical Development: Formulation Development
FFS Projects Projects include formulation development and manufacture of
DP supplies for clinical studiespp
Preclinical Formulation Development IV/oral liquid formulations for PK , pharmacology, and non-GLP tox studies Integration with internal drug discovery capabilities in Medchem Biology DMPK and Integration with internal drug discovery capabilities in Medchem, Biology, DMPK, and
Toxicology Use up-to-date technologies to optimize preclinical formulations to support drug discovery
programs
Technologies for Poorly Soluble Compounds SEDDS formulation Nanosuspension (wet media milling)Nanosuspension (wet media milling) Emulsion, microemulsion, lipid based complex and micelle formulation Solid Dispersions: amorphous form with carrier matrix Solubilizing Agents: cyclodextrins, surfactants, polar organic solvents
CONFIDENTIAL© 2015 China Gateway Pharmaceutical Development
Solubilizing Agents: cyclodextrins, surfactants, polar organic solvents
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Pharmaceutical Development: Formulation Development
Early Phase Clinical Formulation
Powder in Capsule (PIC)
Powder in Bottle (PIB)
Tablet
Li id f l ti Liquid formulation
Oral Solid Technologies
Wet granulation (high shear, fluid bed,
extrusion spheronization)
Dry granulation (roller compaction)
N i i d lid d f i Nanosizing and solid dosage form conversion
Encapsulation, tableting and film coating
0.1 - 5 kg capacity
CONFIDENTIAL© 2015 China Gateway Pharmaceutical Development 28
Pharmaceutical Development: Formulation Development
Formulation Selection Based on
BCS Class
Clinical needs (Oral/IV, immediate/controlled release)
Bioavailability (conventional or enabled) Bioavailability (conventional or enabled)
Dose strength
Single or multiple dose
Drug stability
Dissolution speed
FIH D /C l St th S l ti FIH Dose/Capsule Strength Selection
Common Blend to Cover wide Dose Range
Forced Degradation and Excipient Compatibility
CONFIDENTIAL© 2015 China Gateway Pharmaceutical Development
g p p y
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Pharmaceutical Development: Formulation Development
Fast release system
Tablet, Capsule, Softgel, Orally Disintegrating Tablets, Dispersible Tablets, Effervescent T bl t Ch bl T bl t G l D S i tTablet, Chewable Tablets, Granules, Dry Suspension, etc.
Controlled release system Matrix Membrane controlled Multi-particulate system Osmotic pump system Mini-Tablet in capsules, Multi-layer tablet, etc.
Enabling technology Nano-suspensionp Solid dispersion SEDDS Co-solvents; surfactants; cyclodextrins; etc.
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Pharmaceutical Development: Quality Assurance
Assures overall compliance
Review and approval
cGMP Kilo Lab
A l ti l &
Review and approval
- Change control
- Batch record review
Operation QA
Analytical & PharmaceuticalDevelopments
- Annual product review (APR)
Qualification and validation
Deviation, investigation and CAPAR&D
Manufacturing
Deviation, investigation and CAPA
Compliant handling
Material status control
cGMP Manufacturing Internal and external auditing programs
Management review
Training
CONFIDENTIAL© 2015 China Gateway Pharmaceutical Development
g
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Fengxian QA & EHS Audit Summary Over 35 QA & EHS Audits have been carried since 2011
Auditors include CFDA, “Big Pharma” and specialists including Beckloff Associates and Intertek CFDA Audit Summary
Fengxian GMP Manufacturing Facility has received “Drug Manufacturing Certificate” in 2012 2013 Fengxian GMP Manufacturing Facility has received Drug Manufacturing Certificate in 2012, 2013 and renewed in 2015
China Gateway has applied for several “GMP Drug Manufacturing Certificate” for several APIs manufactured under GMP at the Fengxian site
T E “QP” A dit Two European “QP” Audits Carried out by NNE “QP” auditors and Customer QP auditor according to EMA GMP, Eudralex
Vol. 4, Part II, ICH Q7A and relevant guides using an audit approach similar to FDA’s 6 system inspection approach
Conclusion: Fengxian site is in compliance with EMA regulations to manufacture GMP batches suitable for use in clinical studies in Europe
QA Audit Summary No Critical Observations All “Major” and “Minor” Observations have been addressed
EHS Audit Summary 1 Critical Observation which has been addressed (installed dedicated Air Breathing Supply
system)
CONFIDENTIAL© 2015 China Gateway Pharmaceutical Development
y ) All “Major” and “Minor” Observations have been addressed
32
Quality Management for Analytical Laboratories
Quality management Change control Complaint handling Internal and external auditing Employee Training and qualification Job Description of individuals
Non-conformance Deviations/OOS/OOT/Investigation CAPA
Instrument/equipment qualifications Review and approve Qualification protocol and reports Review and approve Qualification protocol and reports Review and approve Calibration certificate
Contract laboratory audit Document controls
SOP creating revising reviewing approving issuing using retaining withdrawing and abolishing SOP creating, revising, reviewing, approving, issuing, using, retaining, withdrawing and abolishing Document change control
Review and approval Protocols and reports S ifi i & COA f l i
CONFIDENTIAL© 2015 China Gateway Pharmaceutical Development
Specifications & COAs of release testing Notebook and raw data traceability and integrity audit
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Pharmaceutical Development: cGMP Project
Process for the delivery of GMP products
Lab experiments will be carried out based on available procedures and then set up BPR for GMP campaign
Chemistrycampaign.
The BPR and specs will be submitted to customer for the review and approval.
Test and release raw materials, intermediate under GMP control.
Execute the GMP campaign
BiologyToxicology
Execute the GMP campaign
Test and release final batch under GMP control
Delivery final products with COA to customer
Submit the executed BPR to customer
DMPK
Submit the executed BPR to customer
Technical Reports
Per customer’s requests, IND readiness reports include:
Analytical Reports (These should include method development, method validation, reference standard DMPK
y p ( p , ,qualification, etc)
Process development report
Campaign report (cGMP manufacture, etc.)
CONFIDENTIAL© 2015 China Gateway Pharmaceutical Development
Stability report
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2. Infrastructure and Operations2. Infrastructure and Operations
CONFIDENTIAL© 2015 China Gateway Pharmaceutical Development
Infrastructures & Operations: EHS System
Three Levels of EHS Management Systems
Level 1: corporate EHS policy and goal
L l 2 t d d EHS t d (SMP) Level 2: standard EHS management procedures (SMP)
Level 3: standard EHS operation procedures (SOP)
EHS Organization
EHS department: 10 people dedicated team dedicated to EHS training daily lab EHS inspection EHS department: 10 people dedicated team dedicated to EHS training, daily lab EHS inspection, SMP/SOP drafting, EHS process control
ShangPharma safety committee (SPSC): over 120 scientists working together with EHS dept on internal EHS training, weekly EHS audit, and SOP drafting. Forming sub-SPSC committee focusing g, y , g g gon Process Chemistry and CMC to implement SOPs and auditing
Quarterly EHS audit, EHS management system review, EHS training for management team, EHS department and SPSC
Training, Inspection and Audit
Control and Management
Lab chemicals, equipment / facilities, biohazard materials, etc.
CONFIDENTIAL© 2015 China Gateway Pharmaceutical Development 36
Infrastructures & Operations: IP
Corporate practice
Clients owns all data and IP
Confidentiality clauses in each contract
Company policies
Frequent training programs including LNB recording
SOPs in place for IP protection and notebooks, strict information security regulations
Confidentiality agreement with employees; adherence tied to performance review
Infrastructure
Physical security, including badge access
Disabled duplication function on PCs
Domain / proxy control on local computers; limited Internet access
Segregated data storage based on project and access level
Comprehensive e-security platform to safeguard project information
CONFIDENTIAL© 2015 China Gateway Pharmaceutical Development 37
Infrastructures & Operations: IT Support
Secured Communication VPN connection for e-mail and electronic journals C f EMC e-Room for data sharing with client Selected e-mail encryption programs
Network Security CISCO network firewall / Symantec Norton Anti-Virus systemCISCO network firewall / Symantec Norton Anti Virus system Password protected network and workstation access Restricted physical access to network infrastructure
Literature Support SciFinder, Reaxys, Prous Scientific, Thompson Pharma ACS and SciDirect e-journals
Compound Management and Shipping CambridgeSoft compound management system CambridgeSoft compound management system Shipping document preparation Reliable couriers to guarantee timely delivery
CONFIDENTIAL© 2015 China Gateway Pharmaceutical Development 38
Infrastructures & Operations: Reagent Procurement
Organization
Dedicated staff in Fengxian to handle bulk material requests, led by a senior sourcing manager
Supplier Selection based on Supplier Selection based on
Product quality and selection
Cost and terms
On time delivery On time delivery
Company financial data
Customer services
Supplier Management Supplier Management
New suppliers to provide product samples, license, financial data etc.
Regular onsite auditing
Performance tracking Performance tracking
Order Tracking
IT System to track orders, order confirmation and estimated delivery
For high priority items from oversea ordering, E-mail notification to chemists daily
CONFIDENTIAL© 2015 China Gateway Pharmaceutical Development 39
For high priority items from oversea ordering, E mail notification to chemists daily
Infrastructures & Operations: Shipping Quantities up to 10’s to 100’s of Kg – larger quantities will be case dependent A team of well trained staff Green channel custom clearance Internal shipping tracking system Internal shipping tracking system
US Europe Japan
FEDEX 6 days 7 days 5 daysFEDEX 6 days 7 days 5 days
DHL 4 days 5 days 4 days
World Courier 3 days 4 days 2.5 days
Biocair 5 days 5.5 days
All is calendar day, including time required for flight, normal customs clearance and local land-transport. If th ’ t CIQ i ti 2 3 d d d
LuxAir - 4 days -
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If there’s a customs or CIQ inspection, 2-3 more days are needed.
Questions?
CONFIDENTIAL© 2015 China Gateway Pharmaceutical Development