optimization strategies of expression cell line ... 2/304/s304 02_gao feng.pdf · biological drug...
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2nd DIA China Annual Meeting | May 16-19, 2010 | Beijing, China
Optimization Strategies of Expression
Cell Line Construction to Reduce the Biological Drug Development Risk
• Feng Gao, MD, PhD
• AutekBio CO.
2nd DIA China Annual Meeting | May 16-19, 2010 | Beijing, China
• ~ 72% well characterized continuous cell line- rodent origin
50% CHO/ 50% mouse myeloma
• ~ 19% hydridoma
• ~ 8% bacterial
Expression Systems used for Approved Antibody and Antibody-Related Drug
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CHO Mouse
Myeloma
(Sp2/0, NS0)
Hybridoma E. Coli
13 13 7 3
2nd DIA China Annual Meeting | May 16-19, 2010 | Beijing, China
Phase Length of FDA Approved Products
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2nd DIA China Annual Meeting | May 16-19, 2010 | Beijing, China
Monoclonal Antibody New Drug Development & Production Process
Progression
MAb
SelectionInitial
Tests
GLP
StudyPhase I/II
IND
Phase III Commercial
ND
A
20-500mgProduction 1-10g 10-50g 100-1000g kilograms
Requirements Research R&D GMP FDA cGMPFDA inspected cGMP,
no process change
EquipmentsNormal Lab
<50L Bioreactor
<250L Bioreactor
<1000L Bioreactor
3,000-20,000L Bioreactor, multiple lines
Cell Line
Generation (CLG)
Process
Development &
Scaling-up
GMP Production
2nd DIA China Annual Meeting | May 16-19, 2010 | Beijing, China
• Transient expression in bioreactor
– Provide gram level products at early stage
• Higher titer and yield
– “Good” enough cell line and process in short time
• Faster development timeline
– Shorten timeline to clinical trial
• Single-used bioreactor
– Increase flexibility of DS and DP production
……
Current Improvement in Cell Development
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2nd DIA China Annual Meeting | May 16-19, 2010 | Beijing, China
Different Strategies to Speed-up Drug Development Timeline
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CLG & PDPre-clinical
Studies
Phase I & II
Clinical Trial
Phase III
Clinical TrialOn Market
IND
ND
A
Typical
ApproachCell Line Generation (5-12M)
Process Development (>12M)
10-50 grams
Scale-up (10M)
50-100 grams
Scale-up (12M)
100-500 grams
Scale-up 6-6.5 years
Cur. Approach
InternationalPreliminary CLG &
Process Development (12M)
10-50 grams
Scale-up (10M)
50-100 grams
Cell Line Generation &
Process Development (12M)
100-500 grams
Scale-up 5-5.5 years
Available Approach
International
Large-scale transient
expression (3-6M)
10-50 grams
Preliminary CLG &
PD (12M)
50-100 grams
Cell Line Generation &
Process Development (12M)
100-500 grams
Scale-up 4.5-5 years
2nd DIA China Annual Meeting | May 16-19, 2010 | Beijing, China
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NDASelection of Candidate INDPre-clinical Study Phase I/II Phase III
GMP DP ManufacturingCell Development and DS Production GMP DP Manufacturing Scale-up PD for Market Production
NDASelection of CandidateIND
Pre-clinical Study Phase I/II Phase III
“Good” Cell Production“Good” Cell Development
and DS Production
Final Manufacturing Cell Development and
GMP DP Manufacturing
Scale-up PD for
Market Production
NDASelection of Candidate IND
Pre-clinical Study Phase I/II Phase III
“Good” Cell Development and DS Production
“Final” Cell Development & GMP DP Manufacturing Scale-up PD for
Market Production
Transient DS
Production
2nd DIA China Annual Meeting | May 16-19, 2010 | Beijing, China
What is available in China and how can we implement the new technologies in drug development?
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2nd DIA China Annual Meeting | May 16-19, 2010 | Beijing, China
Using Transient Expression for Material Production in Early Stage
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Protein Production Using Transient Methods
Time 7 -10 days;
Host cells CHO, HEK 293
Medium Serum free, ACF
MAb 1 L @ ~500 mg/L
Other low expression
recombinant proteinUp to 20 mg/L
2nd DIA China Annual Meeting | May 16-19, 2010 | Beijing, China
• Gram level mAb production in short time
• Good for candidate screening and selection
• Preliminary PK/PD study
• Toxicity prediction
Large-scale Transient Expression
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2nd DIA China Annual Meeting | May 16-19, 2010 | Beijing, China
Sample data: Delivered “Good” Cell Lines for mAb Production
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2nd DIA China Annual Meeting | May 16-19, 2010 | Beijing, China
• Tens of grams production starts in 6 months after “good”cell line generation and “good” process development
• Ready for preliminary animal studies
• Products close to final target protein drug
• Ready for formulation study
• Ready for analytical method development
“Good” Cell Line and Process for Material Preparation
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2nd DIA China Annual Meeting | May 16-19, 2010 | Beijing, China
Process development, DOE strategy
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Simplex Lattice Design to Optimize Basal Medium
2nd DIA China Annual Meeting | May 16-19, 2010 | Beijing, China
Process development, DOE strategy continued
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Response Surface Design to Optimize Feed Supplement
2nd DIA China Annual Meeting | May 16-19, 2010 | Beijing, China
Process development, DOE strategy continued
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2nd DIA China Annual Meeting | May 16-19, 2010 | Beijing, China
• MCB ready
• Scalable process ready
• Half Kg production
• Ready for pre-clinical study
In-depth Studies for Final Manufacturing Cell Line and Process
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2nd DIA China Annual Meeting | May 16-19, 2010 | Beijing, China
Scaling-Up Using Single-Use Bioreactor
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50L S.U.B. 250L S.U.B.
2nd DIA China Annual Meeting | May 16-19, 2010 | Beijing, China
– To save space and initial investment
– Gives flexibility on process development and material
production
– Short turn-around time for multiple products
Single-used Bioreactor
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2nd DIA China Annual Meeting | May 16-19, 2010 | Beijing, China
Fully integrated DSP capability scales from mg to kg
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2nd DIA China Annual Meeting | May 16-19, 2010 | Beijing, China
• New technologies provide more options for drug
development strategy
• To choose different strategy
– Different application system and different application approaches
– The characteristics of the target protein
– The availability of analytical technology
– Cost and timeline
Summary
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