Académique Documents
Professionnel Documents
Culture Documents
Improvements in Biopharmaceutical
Production and Cost
Relative Cost
approximately 50% of total
0.5
manufacturing costs
¾ Expression level is most
0.3
important parameter in
determining cell culture cost
0.0
¾ Expression level drives required
0 4 8 12
bioreactor capacity and overall
Relative Titer
facility size
World-wide Manufacturing Capacity:
Today and Future
3,500
Reactor Volume ('000 L)
3,000
2,500
2,000
1,500
1,000
500
0
2003 2004 2005 2006 2007 2008
Year
Forecast Industry-wide Capacity Top 8 Potential Volume Drivers Fail
Capacity utilization remains <60% through 2007
Most Probable Case Top 8 Potential Volume Drivers Succeed
Capacity utilization increases to approx. 85% by 2007 Capacity fully utilized by 2007
Estimating Capacity Requirements for MAbs
200 100%
160 80%
Co s t %
¾ Product Requirement:
35 kg/yr
80 40%
¾ 65% overall yield
40 20%
0 0%
0.1 0.3 0.6 1.9 2.8
Product Titre (g/L)
15,000
12,500
Expression Level, mg/L
10,000
10,000
7,500
5,000
2,500
10 100
0
1975 1985 1995 2005 2015
Year
Can Expression Levels be Increased?
¾ MAb expression levels have increased significantly over time
from less than 100 mg/L in 1975 to greater than 3 g/L today
¾ Predicted yields of >10 g/L within the next decade
A 1 139
A 2 334
A 3 585
B 3 1917
B 4 2829
80
70
Titer from pooled CHO
transfectants (mg/L)
60
50 CMVp
40
30 CHEF1p
20
10
0
Ig
Ig
Ig
-2
1
1
b-
E
1-
2-
3-
ab
A
M
P
M
M
14 1400
12 1200
VCD (x 10E6) / viability (%)
10 1000
Titer (mg/l)
Harvest
8 800
6 600
4 400
2 200
0 0
0 2 4 6 8 10 12 14
Days
Media Optimization Strategies
¾ Optimal media for growth and for production must do the
following:
• Provide necessary nutrients at appropriate levels and times
• Keep energy source high so energy production is not rate
limiting
• Buffer to maintain pH within defined process parameters
¾ Regulations now require that media be free of animal-derived
components
• Soy media and other plant sources are under evaluation
• Synthetic media have been developed
¾ Feed rates for glucose and other nutrients can be optimized
¾ Optimization of media and feed strategies can lead to 4 – 10
fold increase in protein expression levels from same cell line
and bioreactor
Media Development and Process Optimization
¾ Process 1
• 300 mg/L
• Used for initial clinical trials through Phase 2
¾ Process 2
• Change feed strategy and optimize media
• 600 mg/L
• Used for Phase 3 and commercial launch
¾ Process 3
• Currently introducing new feed strategy that enables
production at level of >1 g/L from same initial cell line
• To be implemented as post-approval changes