HJB CDMO Introduction (2019)

Hangzhou Just Biotherapeutics (HJB)
Overview

杭州奕安济世
Outline
 HJB Introduction
 Process Development and Tech Transfer
 Manufacturing Facility and Capability
 Quality Management System
 CDMO Scope and Timeline
 Tech Transfer Case Study

杭州奕安济世
Welcome to Hangzhou Just Biotherapeutics (HJB)
a global standard CDMO service company
 Based in Hangzhou, one-hour ride from Shanghai by train
 Our neighbors include Pfizer, Abbott, Merck (MSD), Gilead, forming a hub for biological
manufacturing

杭州奕安济世
About HJB
Just Bio China
Location Hangzhou, China
Leadership team 8 seasoned leaders from Amgen, Genentech, Pfizer, Sanofi, each having >20y
experiences in the development and commercial manufacturing
Investors Arch Ventures, LAV, Just Bio US, Temasek, Taikang Capital, Bank of China, Bank of
Hangzhou, HEDA
Technical focus Full development and manufacturing from early development to GMP commercial
launch
Capacity • Currently 2 x 500 L reactors (200 to 1000L scale), designed for 6 x 500L capacity,
support Fed-batch and Perfusion processes
• 2 x 2000 L lines expansion to be completed by 3Q19
Staff 110 FTE in 2018

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Our Mission
 Bringing more therapies to
market in less time and at
lower cost
 Catalyzing technology and
product development and
manufacturing
 Supply products to markets
around the world for both
clinical and commercial
demand
Strategic
Partnerships
Global
Standard
Innovative
Technology

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HJB competitive advantage - integrated H.DESIGN platform for
rapid development and efficient manufacturing of Biotherapeutics
Developability
Molecule Design
Advance Process
Process Design
H.POD
Plant Design
Through candidate selection
and assessment, proteins are
designed to be potent, stable
and manufacturable
The future is manufacturing
pods that are inexpensive,
flexible and quickly expandable
Integrated cell line, upstream,
downstream and analytical
platforms to rapidly develop high
yielding and robust processes,
specially continuous process
H.DESIGN

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HJB competitive advantage - seasoned leadership team from
top-tier MNCs experienced in PD and manufacturing
25-year process
development, tech
transfer and comm’l
mgf; previously
Amgen, Allergan,
Merck; PhD at Rutgers
Jerry Yang, PhD
SVP, P&PD China
25-year process
development; tech
transfer, comm’l mfg
support; previously
Genzyme/Sanofi; PhD
at MIT
Chris Hwang, PhD
EVP, P&PD US
12-year experience in
biopharma; previously
Amgen process
development; MBA at
UCLA
Chun Li
ED, BD & Pgrm Mgt
20-year biologics
quality and mfg mgmt;
previously Amgen,
Schering-Plough, GSK;
PhD, UNC
Frank Ye, PhD
SVP, Tech Ops
14-year experience in
M&A, IPO, and audit;
previously PwC; CICPA;
ACCA; BS at Sun Yet-
Sen University
Albert Zhu
VP, Business Ops
30 years biopharma
CMC experience;
previously VP at Ipsen,
Genentech; PhD, MS,
BS, MIT
James Leung, PhD
EVP, PD
18-year Amgen and Pfizer,
R&D leadership, BD head
and commercial lead; MBA,
MIT; PhD, U. Ghent
Jonathan Zhao, PhD
Co-Founder / CEO

PROCESS DEVELOPMENT AND TECH TRANSFER

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Process & Product Development overview
 Integrated CMC platforms: from cell line to IND/BLA development
 Highly Effective Team with international company experiences
 World-class Equipment and Laboratory (10,000 sqf), and capacity to be
doubled by 2Q19
 Fed Batch and Continuous Production Capability
 IP Protection

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P&PD capability

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Our Fast-to-IND Cell Line Development Platform
Mini pool
Bulk pool
Month 1 2 3 4
RCB
Transfection
and selection
Single cell cloning
and screening
Stability study & PD
RCB
Transfection
and selection
Pool ScreeningTraditional
approach
Our approach Single cell cloning
and screening
Material generation
and PD
Material generation
and PD
Stability study & PD
Conventional
approach
Our approach
Time to pool 2m 0.5m
Time to RCB 4m 2.5m

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Advantages of stable pool-based material
generation
Stable bulk pool Transient transfection
Timeline 2-3 weeks from transfection 2-3 weeks from transfection
Product consistency Highly similar to final
production cell lines
Higher comparability risk due
to different vector, host and/or
expression system
Titer 0.5 – 2 g/L 50-500 mg/L
Scalability Yes No
Manufacturability assessment Yes No
Suitability for subcloning Yes No

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Upstream Process Development
• End to end upstream process development
• Cell culture process and medium development
• Fed-batch and Perfusion processes
• Cell Bank RCB/MCB/WCB Establishment, stability
• Process scale-up and proof of concept
• Conversion from stainless to single-use
• Bioreactor process optimization
• CMC preparation of filing documents
 12 x 2L, 2 x 10L, 1 x 10L Disposable XDR 10
(6x2L, Ambor and 200L to be added in 1Q19)
 ATF and TFF systems
 Vi-CELL XR, Cedex-Bio, Cobas, Osmo-Pro
Downstream Process Development
Analytical Development
Formulation Development
Technology Transfer
Pre-clinical, PM and RA support

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• Platform technology for monoclonal antibodies (mAbs)
and Fc fusion proteins
• Customized purification processes for recombinant
proteins
• Integrated development scheme from proof-of-concept to
scale-up
• High-throughput process development
• Design of experiments (DoE)
• Resin screening and optimization
• Resin lifetime studies
 4 x AKTA PURE, TFF SPECTRUM KR2i, Nanodrop
(capacity to be doubled by 2Q19)
Technology Transfer

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Technology Transfer
• Method optimization, qualification, and transfer
• In-process testing
• Biochemistry method development and testing
• Bioassay development and testing
• Compendial testing
• Analytical support for process validation and investigations
• Reference standard characterization
• Stability studies
• Comparability Studies
• Analytical Support for Product Profile characterization and
residual testing
 HPLC and UPLC Agilent/Waters Empower 3, CE, UV-Spec,
iCIEF, SoloVPE, qPCR, Envision plate reader, Biacore T200
 LC-MS

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Analytical Methods
• Method development, qualification,
testing
• Release and characterization tests
including physio-chemical
characterization, structural
elucidation.
• Biological function and binding
characterization.
• Comparability exercises
• CMC and analytical support from
drug discovery, drug development,
IND filing, clinical support, all way to
BLA and commercialization.
• Help with shortening developmental
timeline from cell line to IND.
• Critical attribute assignments
• SEC
• IEX, HIC
• CE-SDS (NR and R)
• iCIEF
• rProtein A
• HCP
• rDNA
• peptide map
• Intact/red.mass
• glycan analysis
• charge hetereogeneity ID
• binding assays
• western-blots
• cell based assay

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Bioassay lab and Molecular Biology lab
• Method development, qualification, testing
• rDNA
• HCP
• Binding assay
• Kinetics analysis
• Epitope binding
• FcRs interaction
• Cell-based assay
• Western blot
• Plasmids construction
• Gene cloning test
 Envision plate reader，Biacore T200，7500 Real-Time PCR，
3111 CO2 incubator，NUAIR-NU-543-400S BSC
 DNA Engine PCR，Incubate shaker，UV light box，Electrophoresis
and imaging system

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Technology Transfer
• Preformulation testing
• Formulation development and optimization.
• Container compatibility
• Container closure integrity
• Extractable and Leachable
• Stability protocol development and program
management
• Stability storage and testing
• Stability data trending
• Fill-and-finish support
• CMC activity associated with preparation of
filing documents
 DSC(TA Nano DSC), DLS(DynaPro),
MFI(ProteinSimple 5200), HIAC 9703+

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Study Description Items tested
Developability Roadmap of formulation
development based on
developability score
pH stability, aggregate, activity, Tm, kD,
precipitation, viscosity,
Forced degradation
Preformulation pH, buffer, excipient, Cross effect SEC, activity, iCIEF, CE-SDS, MFI, and critical
PTMs, sterility
Formulation
development
DOE study SEC, activity, iCIEF, CE-SDS, MFI, and critical
PTMs, sterility
Device Stability study, Extractable and
leachable, in-use study
ICP, microscope imagining hydrolytic
resistance, NMR, GC-MS
lyophilization Formulation development and
characterization
Tg’, moisture, XRD, FTIR, SEC, activity

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Technology Transfer
∨ Establish partner joined-committee and PM; set goals,
roles, responsibility and update mechanism
∨ Small scale documentation transfer: Process
description and method procedures
∨ Technical team workshop
∨ Cell bank, process confirmation runs 2L + 10L
∨ Assay transfer and qualification/validation
∨ Scale up process and procedures, documentation for
Tech transfer to mfg.
∨ QA & QC review
∨ Engineering run
∨ Support pilot/large scale runs 200 - 1000L
∨ Bilingual documentation (English and Chinese)
Technology Transfer

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• Pre-clinical study management support
(consulting & CRO management)
• World-class project management experience
• Regulatory support and consultation to meet
FDA & cFDA requirements
• IND filing to cFDA (prepare dossier, follow up)
Technology Transfer

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Drug Substance manufacturing overview
 Multi-product capability
 Currently two cell culture suites
 Two 500L SUB
 Support perfusion and fed-batch processes
 Can produce GMP batches in scales of
200L, 500L and 1000L (pooling)
 Plan to add 2000L CC suite in 2019
 Separate pre and post viral suites
 Single use disposable technology
 Delta V for process automation

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QC capability
 Analytical method optimization, transfer,
qualification and validation
 In-process control, DS& DP lot release test
 GMP stability studies
 Environmental monitoring and PW, WFI, Clean
Steam testing
 Raw material release testing
 Labware LIMS

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 Bioassay lab
 Analytical lab
 Micro lab
 Stability Room
 Preparation Room
 Sample retention Room
 Multi-level storages
 Wash room & Autoclave room
 Clean Area including Bioburden Test, Sterility Test,
Cultivation Positive Test
QC lab functional areas

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HJB Quality Management System
consisting of 7 main systems broken up into multiple subsystems
Production
Systems
Quality
Assurance
System
Laboratory
Control
Systems
Facilities and
Equipment
Systems
Materials
Systems
Packaging and
Labelling
Systems
Development
System

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QMS GMP Document Hierarchy and Implementation-Global
Global QualityPolicy
and Manual
Policies
Global
Glossary
Standards
Global Operating
Procedures (GOPs)
Terry Plant Just China Future Plant
Global QualityPolicyand Manual
Document that contains the Just QualityPolicyanda description
of the QualityManagement System.
Policies andGlobal Glossary
Policies capture critical business andregulatoryrequirements,
and the Glossarydefines terms that must appliedglobally.
Standards and GOPs
Standards define,inmore detail,operational
requirements that must be appliedacross all
sites. GOPs are procedures that applyglobally.
LEVEL 1 – Site
Quality Manual
LEVEL 2 –
System SOPs
LEVEL 3 –
Instructions,
Methods
LEVEL 4 –
Records
Just Global Policy and StandardsJUST GMP Document Hierarchy

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QMS GMP Document Hierarchy and Implementation-HJB
Quality
Manual
Policy
Procedure, Protocols, Forms,
Specifications
Records, Reports, Memoranda
HJB GMP Document Hierarchy
 POL-000016 Quality Plan
 VPP-000004 Validation Project Plan for Just China Hangzhou Facility
 POL-000020 Validation Master Plan of Just China
 POL-000017 Quality Manual
 POL-000019 Risk Assessment
 POL-000018 Change Control
 SOP-000125 Facility GMP Design Qualification
 SOP-000126 Commissioning & Qualification
 SOP-000127 Equipment/System Design Qualification
 SOP-000197 Document Control Procedure
 SOP-000198 Training Program
 SOP-000195 Good Documentation Practice
HJB Policy and Standards

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ComplianceQuest (CQ) provides a GMP compliant computer system
environment for QMS
 CQ was fully validated for QMS
 Manages Quality management workflows, including
 Controlled Document
 Change order
 Nonconformance
 CAPA
 Complaints
 Equipment
 Training

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CDMO Services Scope
Activities Offering
Cell Line Development In house
Cell Bank Creation In house
Cell Bank Safety Testing Subcontract
Cell Bank Storage In house
Process Development In house
Analytical Development and Validation In house
DS Manufacturing In house
Non GMP DP Production In house
GMP DP Production Subcontract – provide tech support and management
Viral Clearance Validation Subcontract - provide tech support and management
Cell Bank Storage In house
DS and DP Storage In house
Regulatory Support In house

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Baseline IND Timeline to drive to 15 months (1 GMP lot)

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Case 1 - Scope of Tech Transfer
Site Tech Transfer and Scale-up
Client X
2x200L
Tox run
Hangzhou JUST Bio (HJB)
2x500L
GMP

杭州奕安济世
Comparable Cell Growth and Productivity Profiles
- Successful scale-up and technical transfer in cell culture performance
0
500
1000
1500
2000
2500
3000
3500
4000
4500
ProductConc.(mg/L)
Product Titer on the Harvest Day
200L (n=2) HJB 500L (n=2)
0
10
20
30
40
50
60
70
80
90
100
0
5
10
15
20
25
30
35
40
0 1 2 3 4 5 6 7 8 9 10 11 12 13 14
Viability(%)
VCD(10E6cells/mL)
Time [day]
Cell Growth Profile
200L (n=2) HJB 500L (n=2) 200L (n=2) HJB 500L (n=2)

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Comparable Impurity Removal Capability
- Successful purification process demonstrated
80
82
84
86
88
90
92
94
96
98
100
ProA IDF AEX HIC VF UF/DF
Purity(%)
SEC Purity
200L (n=2) HJB 500L
1
10
100
1000
10000
100000
Concentration(ppm)
HCP
200L (n=2) HJB 500L
80
82
84
86
88
90
92
94
96
98
100
Purity(%)
Downstream Process
CE-SDS Purity
200L (n=2) HJB 500L
20
25
30
35
40
45
50
55
60
65
70
MainPeak(%)
Downstream Process
cIEF
200L (n=2) HJB 500L

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Method Transfer Policy
 Use the same lot of reference standard, which was also used for the validation and qualification
of analytical method in Method Transfer Donor (MTD).
 Conduct Risk assessment, utilize equivalency acceptance criteria as established in the MTD
validation protocol , compare the data with historic data from MTD.
 Method Transfer Assessment
 Method Transfer Condition Check
 Check the CQV situation of the equipment.
 Method and SOP Document check
 Personnel Training
 Verify the situation of critical materials
 Transfer Evaluation Test Items (depends on method)
 System suitability
 Linearity
 Repeatability
 LOQ

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Analytical Method Transfer
- Successfully transferred to QC
Method* Test Items for Method Transfer Method Transfer Donor HJB QC Comparable
Titer
 System suitability PASS Pass
Yes
 Specificity Pass Pass
 Repeatability (RSD≤5%) 1% (n=6), 3%(n=12) 1%(n=3), 2%(n=9)
 Linearity R2>0.99 R2=1.00 R2=1.00
 LOQ, 0.4 mg/mL Recovery: 103% ; RSD: 2% Recovery: 103% ; RSD: 1.3%
Bioburden
 Method Confirmation
 No growth in negative control group
0 cfu/filter 0 cfu/filter
Yes
 Positive control: 10~100 CFU/filter 19, 40cfu/filter 20,36 cfu/filter
 Recovery: 50%~200% 70~153% 75%, 155%
Protein
Concentration
 System suitability
 Specificity: blank≤0.05
0.00 ABS/mm 0.00 ABS/mm
Yes RS Accuracy: 95~105% 101% 98%
 Repeatability (L1,3,5,RSD≤3%) 0%,0%,1% 0%,1%,0%
 LOQ (Linearity and range) 16~24mg/ml, R2=1.00, RSD≤1% 16~24mg/ml, R2=1.00, RSD≤1%
Cell Based Activity
 System suitability Pass pass
Yes
 QC sample Accuracy, potency%: 80%-125% 97~106% 98%~101%
 Linearity R2>0.95 0.9984 0.9946
 Repeatability: RSD ≤20% 5% 6.8%
* Representative methods

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Comparable Quality of Drug Substance
Tech Transfer
Donor
HJB Comparable
Quality Attributes Specification 200L Scale (n=2*) 500L Scale Yes/No?
Purity by SEC (%) ≥ 90.0 99.5±0.5 99.3 Yes
Purity by cIEF (%) ≥ 40.0 61.2±3.0 60.4 Yes
Purity by Non-Redu CE-SDS (%) ≥ 93.0 98.8±0.7 99.7 Yes
HCP （ppm） ≤ 150 70±4 6 Yes
Residual ProA (ppm) ≤ 10 ≤1.6 1 Yes
DNA (pg/mg) ≤ 5.0 <0.3 <1 Yes
Cell Based Activity (%) 50-150 103±0 101 Yes
* Data are presented in mean ± 1 standard deviation.

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Case 2 - Scope of Tech Transfer
Site Tech Transfer and Scale-up
Client Y
3x200L
Tox run
Hangzhou JUST Bio (HJB)
1x500L
GMP

杭州奕安济世
Comparable Cell Growth and Productivity Profiles
- Successful scale-up and technical transfer in cell culture performance
0
10
20
30
40
50
60
70
80
90
100
0
5
10
15
20
25
30
35
40
0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17
Viability(%)
VCD(10E6cells/mL)
Time (day)
Cell Growth Profile
200L (n=3) HJB 500L (n=1) 200L (n=3) HJB 500L (n=1)
0
500
1000
1500
2000
2500
3000
3500
4000
ProductConc.(mg/L)
Product Titer on the Harvest Day
200L (n=3) HJB 500L (n=1)

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Product Recovery
- Comparable downstream process yield
0
20
40
60
80
100
120
Recovery(%)
Process Step
Downstream Process Step Recovery
200L (n=3) HJB 500L (1st GMP)
0
20
40
60
80
100
120
Recovery(%)
Overall Recovery
200L (n=3)
HJB 500L (1st GMP)

HJB: Integrated Process Development
and Manufacturing Partner

HJB CDMO Introduction (2019)

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