The document summarizes data from 12 biopharmaceutical flexible facility projects. Common elements included the use of single-use bioreactors and technology to increase flexibility. Most facilities used campaign manufacturing. Expansion strategies included equipment swapping, fitting out unused space, and installing additional single-use bioreactors. The majority of facilities were designed to enable implementation of new technologies like perfusion and antibody drug conjugates.

1. Flexible facility
success
Case study of 12
flexible facility
biopharm projects
Frank Nygaard
May, 2015

2. 2
Content
The 12 projects – common denominators
The 12 projects – the data set
Process design
Facility design and manufacturing strategy - campaign versus concurrent manufacturing
Facility design
Single-use implementation
Capacity expansion strategies
Flexible technology integration
Summary

3. The 12 projects
Common denominators
3
Single-use technology: Enabler for flexible manufacturing
• Decouples the process from the building
• No complex distribution matrices as connections are flexible
• Media and buffer supply is configured to the given process
• Can start with only 500L bioreactor train and expand rapidly
• 2000L footprint is not drastically larger than 500L footprint
Design basics
• NNE Pharmaplan Bio on demand™ with flexibility as key driver
• Facility designs are for multiproduct manufacturing
• Single-use bioreactors utilised for mammalian fed-batch cell cultivation
• Other process and support systems may be single-use, stainless steel or hybrid systems

4. The 12 projects
The dataset
4
Basic of design Location
#1 2011 China
#2 2012 Taiwan
#3 2012 Russia
#4 2012 China
#5 2012 Denmark
#6 2013 China
#7 2014 Germany
#8 2014 Brazil
#9 2014 India
#10 2014 Brazil
#11 2015 Malaysia
#12 2015 China
Pilot
(3)
Launch (3)
Commercial
(6)
Manufacturing
scope
Basis for data evaluation

5. Process design
5
Model processes for design
• “Protein”: 58% (incl. mAbs)
• mAb platform: 42%
Batch size
• Pilot scale SUB: 500 – 1000L
• Launch scale SUB: 1000 – 2000L
• Commercial scale: 2000L 1)
Manufacturing strategy
• Campaign manufacturing: 83%
• Concurrent manufacturing possible: 17% 2)
Facility
Design
Process
design
SUB
size
SUBs
per line
#1 Launch “Protein” 2000L 1x
#2 Pilot “Protein” 500L 2x
#3 Launch mAb 2000L 2x
#4 Commercial mAb 2000L 4x
#5 Pilot “Protein” 1000L 4x
#6 Launch mAb 1000L 2x
#7 Commercial “Protein” 2000L 6x
#8 Commercial mAb 2000L 4x
#9 Commercial “Protein” 2000L 2x
#10 Pilot mAb 1000L 1x
#11 Commercial “Protein” 2000L 2x
#12 Commercial “Protein” 2000L 7x
1) “Scale out” of SUBs to increase batch size included in 29% of commercial designs
2) Concurrent: Manufacturing of different products in cell culture possible at the same time

6. Facility design and manufacturing strategy
Campaign versus concurrent manufacturing
• Strategic use of manufacturing strategy in the
facility design
• Campaign-based manufacturing
• More upstream lines than downstream
• Concurrent-based manufacturing
• Less upstream lines than downstream
6
Downstream DownstreamUpstream
Downstream
(1 week)
Cell culture
(3 weeks)
DownstreamUpstream Upstream

7. Facility design
7
Construction design
• 100% stick build (with modular construction evaluated in 17%)
Process design
• 92% traditional design with seed lab, cell culture, initial and final
purification
• 8% “Ballroom” concept (with shared cell culture and purification)
Cleanroom classification
• Seed lab Class C (Iso 7)
• Cell culture Class D (Iso 8)
• Initial purification (pre-virus) Class C (Iso 7) or Class D (Iso 8)
• Final purification (post-virus) Class C (Iso 7)

8. Single-use implementation
8
Upstream
• Bioreactor: 100%
• Harvest clarification: 66%
• Media preparation: 75%
• Media hold: 92%
Downstream
• Intermediate product hold: 92%
• Process equipment: 17%
• Buffer preparation: 75%
• Buffer hold: 92%
1) SU: Single use chromatography and UF/DF skids not considered
Facility
design
Total
capacity
Technology 1)
#1 Launch 2x 2000L SU
#2 Pilot 2x 500L SU
#3 Launch 2x 2000L SU
#4 Commercial 4x 2000L SU
#5 Pilot 4x 1000L SU
#6 Launch 2x 1000L SU
#7 Commercial 6x 2000L Hybrid
#8 Commercial 12x 2000L SU
#9 Commercial 4x 2000L Hybrid
#10 Launch 1x 1000L SU
#11 Commercial 8x 2000L Hybrid
#12 Commercial 14x 2000L Hybrid

9. Capacity expansion strategies
9
Equipment
swap
Drop blockFitting out

10. Capacity expansion strategies
10
• Facility designs with expansion strategy: 92%
• Equipment swap: 25%
• Fitting out: 58%
• Drop block: 17%
• Capacity expansion: 100 - 400%
Equipment
Swap
DropBlock
Fitting Out
Phased expansion Initial
capacity
Final
capacity
#1 Equipment swap 2x 1000L 2x 2000L
#2 Equipment swap 2x 200L 2x 500L
#3 Fitting out 1x 2000L 2x 2000L
#4 Drop block 2x 2000L 4x 2000L
#5 Fitting out 2x 1000L 4x 1000L
#6 Fitting out 1x 500L 2x 1000L
#7 Fitting out 2x 2000L 6x 2000L
#8 Fitting out/Drop block 4x 2000L 12x 2000L
#9 Fitting out 2x 2000L 4x 2000L
#10 Fitting out 1x 500L 1x 1000L
#11 Equipment swap 8x 500L 8x 2000L
#12 14x 2000L 14x 2000L

11. Flexible technology integration
11
Facility design Perfusion F&F ADC
#1 Launch X
#2 Pilot
#3 Launch
#4 Commercial X
#5 Pilot X
#6 Launch X
#7 Commercial X
#8 Commercial
#9 Commercial X X X
#10 Launch X
#11 Commercial X X
#12 Commercial X
• 83% include a flexible fed-batch facility design:
• Fed-batch to perfusion: 42%
• End-to-end manufacturing (API+F&F): 50%
• Antibody Drug Conjugate (ADC): 8%

12. Summary
12
• Single-use technology is to key enabler for flexibility
• Hybrid solutions prevalent in the facility designs for commercial production
• “Traditional” layout for upstream and downstream – ballroom design not embraced yet
• Expansion strategy considered in facility designs
• Design for implementation of new technologies

13. For more information
13
Frank Nygaard
Senior Technology Partner
T: +45 3079 9785
fkny@nnepharmaplan.com
Connect with Frank Nygaard on LinkedIn
Blog by Frank Nygaard: Where does flexibility really matter?:
http://www.nnepharmaplan.com/insights/on-the-move/where-does-flexibility-really-matter/
www.nnepharmaplan.com