advanced biopharmaceutical technology platform: role of dcb to the biotech industry … ·...
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Advanced Biopharmaceutical Technology Platform:
Role of DCB to the Biotech Industry in Taiwan
Wei-Kuang Chi, Ph.D. Executive Director, Institute of Pharmaceutics
Development Center for Biotechnology 2018/08/03
Development Center for Biotechnology 2
Mission , Vision and Aims
• Mission: To facilitate the development of Taiwan's biotech industry
• Non-profit organization founded in 1984
– Building the infrastructures for R&D and business – Developing key biotechnologies – Training professional workforces – Coordinating resources from industry, government, academia,
and research institutions. • Aims:
– Be the “best partner for biotech industry” – Assume the role of “second baton” for value-adding and
incubation in the industrial value chain. – Facilitate commercialization of products through technology
transfer & IP licensing, collaborations, and entrepreneurship 3
New Drug Development Biological, Chemical , Botanical Drugs & Cell Therapy
Pre-Clinical Support Pre-clinical Development Service for both Academia & Industry
Business Promotion Technology Commercialization & Market Development
Core Business
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Lead Discovery
Validation Optimization
Preclinical ADME Tox
IND Clinical Trials Phase I, II, III
NDA Market
Innovative projects
Clinical Trial
R&D Core in DCB
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R&D Integrated Competency
• Drug Design & Synthesis and Formulation • DM/PK (ADME), Animal Pharmacology and Toxicity Testing • Process development for GMP Production
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cGMP Biopharmaceutical Pilot Plant Facility
Mammalian cell culture and microbial production of biologics for clinical Phase I/II trials
cGMP certificate by DOH, TAIWAN FDA Drug Master File (No. 19164) PIC/S international cGMP compliance BioPharma Asia’s Best CMO Award (2011)
Protein Drug / Manufacturing Service
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2013.4
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Microbial Secretion System
Continuous Biomanufacturing
High Yield CHO Expression System
Process Development of
CAR-T
Bioengineering Group – Life after CGMP BPPF Spin-off on 2013.4
High-Yield CHO Expression System
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CHO Cells
Preferred host for production of biotherapeutic glycoproteins • Post translational modifications-human like N-glycan • Capacity for correct folding and secretion • Low transmission of viruses • High protein yield • Robustness towards pH, temp, oxygen level and pressure variations • Long FDA history
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During 2015-2017, 16/22 of FDA approved mAbs are produced in CHO
https://www.igeahub.com/
Top 20 Drugs in the World (2017)
DCB CHO Expression Systems
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CHO-C Expression System
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Fed-batch culture: CHO-C vs. DXB11 90.3
62.2
CHO-C derives from DXB11
cGMP produced and tested CHO-C cell line
Proprietary Vector (FTO)
Document of CHO-C cells is ready
Multiple IP protection
Process development and optimized medium
Technical support from our CHO-C platform R&D team
One time fee Products Unlimited Milestone and Royalty Free
Process Optimization
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✦Process improvement
✦Antibody production
Batch -6Day v.s. Fed-batch-14Day
5-14 x improvement Titer : 1~4.5g/L
Qp: 10~30
Process Development: Scale Up
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CHOK1
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bilit
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ells
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250ml mini-bioreactor 5L Bioreactor XDR-50L 250ml mini-bioreactor 5L Bioreactor XDR-50L
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Tite
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Continuous Biomanufacturing THE FUTURE OF DRUG MANUFACTURING
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The FDA Perspective
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http://www.in-pharmatechnologist.com/Processing/FDA-calls-on-manufacturers-to-begin-switch-from-batch-to-continuous-production
August 1, 2018/ Amgen breaks ground on $200M next-gen biopharma plant in Rhode Island, expected to be completed by 2020 The facility will feature a number of new manufacturing technologies and equipment that is smaller and portable, allowing Amgen to more quickly respond to changing demands in producing new medicines will allow the plant to be constructed in about half the time as well as reduce operating costs
The Benefits of Continuous Manufacturing
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OPEX: operating expenses
CAPEX: capital expenses
Cost reduction!! Smaller footprint!!
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Integrated Continuous Bio-manufacturing and Purification
Higher efficiency
Cost down
High product titer
Saves processing times
Constant product quality
Cell culture perfusion 2 g/L/day Purification throughput 100 g IgG/day
Process Development of Chimeric Antigen Receptor (CAR)-T Cells
CAR-T Cell Therapy
https://www.cancer.gov/publications/dictionaries/cancer-terms/def/car-t-cell-therapy
2017 CD19 CAR-T approved Novartis Kite
Manufacturing Process of CAR T Cells
Totally, ≥ 109 T cells might be required.
Technique Development for CAR-T Cell Therapy
CAR-T cells
Convert IgG to scFv
Design of CAR
Viral vector preparation
CAR T cell preparation
Nonclinical experiment
(POC)
Clinical trial (POC)
Hospital/ Clinical trial center
Cell manufactory GTP lab
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Preparation of CAR-T Cells
The Growth and CAR+ Population of CAR-T Cells were Increased in our Modified Condition
Modified condition Initial condition Initial total T cell number: ~1 x106 cells
(N) Expansion fold
CAR-T cell number
CAR+ percentage
CAR+
(GFP
+) c
ell n
umbe
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CAR+
(GFP
+) p
erce
ntag
e (%
)
CAR+
(GFP
+) p
erce
ntag
e (%
)
anti-CD19 CAR-T cells
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Result in DCB
CAR-T Summary
We have established a serum-free culture platform to expand primary T cells and CAR-T cells to 20-125 folds of initial cell number in a 6-7-day culture (10-day process)and to 100-2500 folds in a 2-week culture (14-day process) ex vivo.
The T cell subsets in this serum-free culture condition were majorly early differentiated Th1 and CTLs.
Potential advantages: It can reduce the requirement of initial T cell number to perform basic
research or clinical treatment. Short operation time and high cell density could lead to the reduction of
occupancy of equipment and consumption of materials. Control of cell subsets at early differentiation stages might increase the
persistence and potency of CAR-T cells.
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Microbial Secretion Expression Platform
Microbial Secretion Expression System
• Escherichia coli – Periplasmic – Extracellular – Intracellular
• Pichia pastoris – Extracellular
• Methanol induction • Constitutive
Methanol Feeding Profile Optimization in Mini-Fermentor
The pH and DO profile
NP2Run_Control
NP2Run_Higher
Information for NP2 Run fermentation process
pH = 6.0 DO = 30% (cascade) Agi.: 800~1500 rpm Temp.: 30℃ Initial volume: 100 ml
※ The higher methanol medium feeding rate can achieve 1176 mg/L scFv antibody fragment at 120 hours.
The optical density profile
Induction Strategies of Pichia pastoris in 5L Fermentor
Methanol feedback control system Dissolve oxygen feedback control system
The optical density profile of different induction strategy by 5 L fermentation Dissolve oxygen feedback control system Methanol feedback control system
Batch Glycerol feeding Methanol induction
The amount of induction medium consumption: Methanol feedback control: 1440 ml. Dissolve oxygen feedback control: 1118 ml. Methanol feedback control as induction medium feeding strategy can produce higher titer then dissolve oxygen feedback control system.
Production titer at 120 h is 1.01 g/L
Production titer at 120 h is 0.80g/L
P. Pastoris Secretion System
Protein yields up to 1 g/L Number of secretion signal peptides: 6 sequences Number of promoters: 2 Selection method: Zeocin Time: 6 weeks
E. coli Secretion System
Protein yields up to 0.1 g/L Number of secretion signal peptides: 3 sequences Number of promoters: 3 (T7, PhoA, Tac1) Host: DE3 and non-DE3 Time: 7~8 weeks
DoE mediated Process Development
pH Dissolve oxygen
Feeding strategy
Medium
Temperature
DASGIP: 250 ml Fermenter 5L Fermenter
Microbial Secretion System
The Improvement of Production Yield in E. coli and P. pastoris
Deep well screening 50 ml shake flask 250 ml mini-fermenter 5L fermenter
E. coli secretion system
0.5 mg/L 10 X 5 mg/L 20 X 100 mg/L 1 X 100 mg/L
1 mg/L 2-10 X 5 mg/L 10-200 X 1100mg/L ~1 X 1000 mg/L
P. Pastoris secretion system / Methanol induction
P. Pastoris secretion system / Constitutive
>0.64 mg/L 4 X 2.56 mg/L ~12X 30 mg/L 1 X 30 mg/L
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Technology Platform Summary
Acknowledgement
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Funding and Support
CHO consortium Dr. Wei-Shou Hu’s Group
Bioengineering Group Leader: Dr. Wei-Kuang Chi
Business Development
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ITIS BPIPO DCC NBIC BD
From Benchtop to Commercialization
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Incubator/ Accelerator
Market analytics & intelligence
Drug Commer-cialization
Business Development
One-stop service window
Drug Commercialization Center
Nankang Biotech Incubation Center
IEC Innovation & Entrepreneur Core
Platforms for Start-ups/ Spin-offs
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南港生技育成中心 NanKang Biotech Incubation Center , NBIC
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NanKang Biotech Incubation Center Location NanKang Software Park Phase 2 Build F 17F 坪數
Incubation:19 16,265 sq ft
Public facility: open lab, Library, meeting rooms 26,993 sq ft Total 43,258 sq ft
Sector Pharmaceutical, Medical device, Biotechnology etc..
NanKang Biotech Incubation Center • Founded in 2004 by SMEA, MOEA • Operated and Managed by DCB • Located in NanKang BioPark in Taipei City
– Total 1,216 pin (43,258 sq ft) – 19 rooms – Public facility: open lab, Library, meeting rooms
• Incubated more than 70 companies in the past 14 years
• Currently 19 residents – 13 pharmaceutical – 2 Medical device – 3 CRO – 1 AI
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Integrated Platform of DCC
Academic-Industry Collaboration
Technology Licensing
Start-up Company
International Marketing
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Will be located in Building C of NBRP
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E
B A
C F
G
D
中研院
A 生醫轉譯研究中心
B 核心主題研究中心
C 創服育成中心
D 生物資訊中心
經濟部 E 生物技術開發中心
衛福部 F 食品藥物管理署
科技部 G 國家實驗動物中心
F
Spin-offs of Pre-Clinical R&D Teams from DCB
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Spin-off Companies from DCB
1984.3 Founded
1987.1 Chang-Hsin
Headquarters Inaugurated
1994.1 Xizhi R&D Area Building Constructions Finished
2004.5 Headquarters moved
from Chang-Hsin to Xizhi and Nangang District
2011.1 GLP Toxicology Lab (acquired by QPS Taiwan)
2013.4 CGMP Biopharmaceutical Pilot Plant Facility acquired by EirGenix, Inc.
2016.10 Spun off TFBS Bioscience, Inc. for GLP biosafety testing
2018.5 Headquarters moved
from Xizhi District to and NBRP
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1984 保生製藥
2000.6 台灣尖端生技
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Center of Toxicology & Preclinical Sciences
GLP Lab Facilities (OECD GLP、DOH GLP)
Accreditations: AAALAC (Association for Assessment and Accreditation of Laboratory Animal Care), TAF ISO17025, TAF OECD GLP
81 ISO 17025 Test Services
cGMP Biopharmaceutical Pilot Plant Facility
Mammalian cell culture and microbial production of biologics for clinical Phase I/II trials
cGMP certificate by DOH, TAIWAN FDA Drug Master File (No. 19164) PIC/S international cGMP compliance BioPharma Asia’s Best CMO Award (2011)
Protein Drug / Manufacturing Service
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GLP Testing Facility for Biological Safety
Protein Drug / Safety Testing
Cell Bank Characterization
Virus Clearance Validation
Bulk & Lot Release Testing
Bioassay Development
Clinical Sample Analysis
Recent Case : 510(K) Accreditation for Biogenic Technology, Inc.
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Successful Examples（2011～2017）
Start-up
醫萊發生技(股)公司
得生製藥股份有限公司
宥勝生技
潤惠生技
Academic Industrial Collaborations
生脈生技
Licensing
昌固生物科技
浩宇生醫
唯醫生技
瑞河國際有限公司
台新藥股份有限公司
National Biotechnology Research Park DCB expands into NBRP to join the mission of enhancing next-generation global competiveness of biopharmaceutical industry of Taiwan.
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Eco-Friendly Campus Innovation/ Incubation/ Integration
A: Translational Medicine Center B: Core Thematic Center C: Innovation Incubation Center D: Bioinformatics Service Center E: Biotechnology Development Center F: Food and Drug Administration G: National Animal Center Academia Sinica (0.5km away)
Source: BioTaiwan Biocluster country forum 2016 50
Basic Research
Translational Med/
Bioinformatics New Drug
Development
Preclinical Study
Regulatory Office
Commercialization /Incubation
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DCB, your trusted partner
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Thank You!