Optimization Strategies of Expression Cell Line ... 2/304/s304 02_gao feng.pdf · Biological Drug Development Risk ... Different Strategies to Speed-up Drug Development Timeline Drug

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.


• ~ 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

Drug Information Association www.diahome.org 2

CHO Mouse

Myeloma

(Sp2/0, NS0)

Hybridoma E. Coli

13 13 7 3


Phase Length of FDA Approved Products



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


• 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



Different Strategies to Speed-up Drug Development Timeline


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 &


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 &


100-500 grams

Scale-up 4.5-5 years



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


What is available in China and how can we implement the new technologies in drug development?



Using Transient Expression for Material Production in Early Stage


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


• Gram level mAb production in short time

• Good for candidate screening and selection

• Preliminary PK/PD study

• Toxicity prediction

Large-scale Transient Expression



Sample data: Delivered “Good” Cell Lines for mAb Production



• 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



Process development, DOE strategy


Simplex Lattice Design to Optimize Basal Medium


Process development, DOE strategy continued


Response Surface Design to Optimize Feed Supplement


Process development, DOE strategy continued



• MCB ready

• Scalable process ready

• Half Kg production

• Ready for pre-clinical study

In-depth Studies for Final Manufacturing Cell Line and Process



Scaling-Up Using Single-Use Bioreactor


50L S.U.B. 250L S.U.B.


– To save space and initial investment

– Gives flexibility on process development and material

production

– Short turn-around time for multiple products

Single-used Bioreactor



Fully integrated DSP capability scales from mg to kg



• 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


Documents

Optimization Strategies of Expression Cell Line ... 2/304/s304 02_gao feng.pdf · Biological Drug Development Risk ... Different Strategies to Speed-up Drug Development Timeline Drug