Single Use System was first used about two decades ago as for dialysis and IV fluid. This technology has grown over the last ten years into a major asset for cell cultivation, fluid processing, fluid storage and delivery systems. They now range from a few liters to thousands of liters.

1. Major benefits of single use
systems in the
Biopharmaceutical Industry :
An Evolving Technology
Ahmad J. Shahidi
Senior Engineering Consultant
for
INTERPHEX2008

2. Historical Benefits of the Stainless Systems
• Excellent regulatory compliance
• Excellent corrosion resistivity over broad range of
chemicals
• Very flexible material
• Very durable material
• Easily cleaned
• Readily Steam Sterilizable

3. Stainless Market Update
Prices Have Simply Gone “Through
the Roof”

4. What is causing the surge in
stainless steel pricing?
• Strong world demand for SS combined with the
weak US dollar has reduced amount of SS
imported into the US.
• Very Strong China GDP Growth in 2006
• China consumed - 1/3 of the world’s Steel
• China consumed - 1/4 of the world’s Copper
• China consumed - 1/5 of the world’s Aluminum

5. Alternative to SS:
Single Use Bioprocess Systems

6. Alternative – Single Use Systems
This type of bag was first used about two decades
ago as for dialysis and IV fluid. This technology has
grown over the last ten years into a major asset for
cell cultivation, fluid processing, fluid storage and
delivery systems. They now range from a few liters to
thousands of liters.

7. Application was limited to:

8. A Growing Presence…
2005 2006
Dead-End Filters 79% 90%
TFF Filters 44% 72%
Tubing 56% 85%
Small Bioreactors 21% 59%
–4th Annual Report and Survey of Biopharmaceutical Manufacturing, Capacity, and Production ©2006
BioPlan Associates, Inc.

9. Incentive For Adoption of Disposable
Systems
Fast Product Changeover = Higher Productivity:
– To change a bag takes minutes
– To CIP/SIP a vessel:
Clean ( 60 min )
Sterlization (2 to 4 hours)

10. Incentive For Adoption of a Disposable
System (cont.)
• No CIP or SIP between batches/products
• No risk of contamination between batches/products
• No cleaning validation
• Reduced total investment cost
• Reduced operating cost for clean utilities
• Rapid speed to market

11. Incentive For Adoption of a Disposable
System (cont.)
• Excellent compatibility with various biological
solutions
• Excellent test result for extractable with various
biological solutions
• Excellent regulatory compliance through totally
closed systems
• Enhanced security through totally closed
systems

12. Applications: Wave Bioreactor

13. Applications: Single-Use Bioreactors
S.U.B. XDR

14. Applications: Solution Storage

15. Applications: Mixers : SUM

16. Applications: Solution Prep

17. Applications: Centrifuge
Test units for 8.5 and 25 lpm,
target availability ~Q4-2008…

18. Applications: Filtration

19. Applications: Solution Freeze and Thaw
(Celsius System)

20. Applications: Bulk Filling/Filtration Station

21. Applications: Purification

22. Applications: Purification

23. Applications: Aseptic Connectors
Tube Welders & Tube Sealers
– Requires use of thermoplastic tubing.
– Can be used to aseptically fuse two tubes
together or to seal tubing off/closed.
– A variety of welders & sealers are available
on the market from:
– Sebra, Wave, CPT, Terumo, others
– Issues:
• Generally can not make a “wet” seal/weld.

24. Fluid Transfer - Connection
Tube Fusers and Aseptic Connectors

25. Applications: Tubing Fluid Flow Rate
Tubing OD Flow Rate
(lpm)
¼” 1
5/16” 1 1/2
7/16” 2
½” 3
5/8” 7
¾” 10
7/8” 15

26. Various Tube Welders (Fusers) and Sealers

27. Applications: Aseptic Connectors
• Aseptic Connectors:
– Pall KleenPak Connector
– BioQuate Connector
– Millipore S2S Connector
• All can be used making a sterile
connection in “gray space” or in clean
room.

28. Applications: Transfer Between Zones

29. Applications: Aseptic Fluid Transfer

30. Issues, Risks & Challenges
• Technical Limitations
– Not recommended to be used with organic solvents
– Not recommended for high heat transfer (removal) operations
– Not recommended for high mixing rate operations
– Scale – Limited to lower volumes
– Max Fluid transfer rate limited with Tubing size
• Experience
– Bag technology may be more susceptible to ripping, puncture and
leakage
– Limited experience in Commercial Operations
• Increased Vendor Reliance
– Limited Availability of components and parts
– Limited Selection of suppliers
– Increased Quality Burden for Vendor Qualification

31. How do we disposed of the bags?
• Recycling is the obvious first choice
• Non-Hazardous Contents: Landfill
• Hazardous Contents: Hazardous waste disposal
• Biohazard Contents: Decon Autoclave, then landfill
• Alternative: Incineration

32. Case Study 1 – Hybrid Approach

34. Linking SS to Disposable Systems

35. Linking SS to Disposable Systems

36. Benefits : Reduced Circulation Corridors
HARVEST PRE-VIRAL POST-VIRAL
INOCULUM CULTURE
ROOM PURIFICATION PURIFICATION
ROOM
ROOM
CLEAN CORRIDOR
PRE-VIRAL POST-VIRAL
PURIFICATION PURIFICATION
INOCULUM CULTURE
HARVEST
ROOM ROOM
ROOM

37. Benefits : Reduced Clean Processing Areas
HARVEST PRE-VIRAL POST-VIRAL
INOCULUM CULTURE
ROOM PURIFICATION PURIFICATION
ROOM
ROOM
CORRIDOR -
MATERIAL HALL
PRE-VIRAL POST-VIRAL
PURIFICATION PURIFICATION
INOCULUM CULTURE
HARVEST
ROOM ROOM
ROOM

38. Capital Equipment Cost Comparison ($ X 1000)
Single Use Conventional
Process Equipment 10,300 12,800
Process Utility 2,100 3,400
Process Piping 3,100 4,300
Instrumentation & Control 1,800 2,300
Electrical 1,900 2,600
Insulation & Painting 800 900
Taxes, Frieght & Erection 1,200 1,800
Total Installed Equipment 21,200 28,100
Savings 24.5%

39. Total Installed Costs ($ X 1000)
Single Use Conventional
Total Installed Equipment Cost 21,200 28,100
Building Costs 26,500 28,900
Indirect Costs 11,700 14,000
Commissioning Costs 715 855
Validation Costs 1,431 1,710
Total Installed Cost 61,546 73,565
Savings 16.3%

40. Capital Breakdown
80,000
70,000
Validation
60,000
Indirect Cost
50,000
Building Cost
40,000 Process Installation
30,000
20,000
10,000
0
Single Use Conventional

41. Conclusion - Case Study 1:
• Reduced capital equipment costs
• Reduced cleaning costs
• Reduced process utility costs
• Reduced labor costs
• Reduced validation costs
• Reduced assembly costs
• Increased Productivity

42. Case Study 2 – Transforming to Total
Single-Use System (TSUS)
Reduce Capital & Start Up Costs By 50%

43. Transforming to Total Single-Use System
Transforming Bio-manufacturing
processes to single-use-equipment will
entail more than simply replacing steel
with plastic. It means changing the way
manufacturers think about processing,
(i.e. changes in SOPs and regulatory
approaches).

44. Guiding Assumptions
• Maximize the Application of Single Use Equipment
• Minimize Segregated Clean Room Spaces
• Maximize Operational Flexibility
• “Push the envelope” on Regulatory requirements
• Closed System for all Unit Operations

45. Single-Use, Closed Systems Definition
a work-in-progress
Assemblies of components
that are totally sealed and
sterilized at the point of
manufacture,
with in-line filters and/or
aseptic connectors
included in the sets made
for single use,
that allow these assemblies
to remain contaminant-
free throughout their
lifecycle of use.

46. Examples of Gamma Radiated Closed
Systems
• Bioreactor cell-bags with pre-sterilized tubing and filter
sets
• XDM or S.U.M. mixing bags with pre-sterilized tubing
and filter sets
• Solution bags with pre-sterilized tubing and filter sets
• Solution filter with pre-sterile connection sets
• Novseptic sampling or manifold tubing systems

47. Advantages of Processing in Closed
Systems
• Prevents Cross Contamination
• Protects Products and Operators
• Minimizes the Impact of HVAC Air Flows and
Pressure Differentials
• Allows for Concurrent Operations

48. Concerns - Issues
• Sampling ports
• Connection ports

49. Chromatography System
Connections Connections
Vent
F
Packing
F
Chromatography System
to Sump

50. How Can a Closed Chromo System be
Achieved?
• Procure Pre-sterile Components, where possible.
• Use Double Bags for Cleaned and Sterilized
Components.
• Perform Column Packing, if required, under
unidirectional airflow.
• Assemble Column Controller under unidirectional airflow.
• Make Connections via tube fuser or use pre-sterilized
connections such as Kleenpak, Sart(Raft) or Bioquate
Next page…

51. How Can a Closed Chromo System be
Achieved? (cont.)
• Tri-clamp Connections with Steam Block Valving or
Colder Systems
• Closed Sampling Devices such as Novaseptic Sampling
System
• Validated Simultaneous Chromatography Column
System Cleaning and Regeneration Cycle.
• Undisrupted Column Operation from Equilibration
through Regeneration.

52. Reduce Capital & Start Up Costs By 50%
Closed
System
Open
System

53. Reduce Capital & Start Up Costs By 50%
Conventional Plant Total Single Use Equipment

54. Facility Layout Considerations
• For flexibility purposes, modular clean room panels
have been used defining the perimeter support
rooms.
– Clean room type modular panels were chosen
because of the ease with which the rooms can be
reconfigured to meet changing requirement.
• The ceiling system also has been a modular clean
room style system that would allow for integration
with the wall panels and some degree of walk-ability
for maintenance purposes.

55. Capital Equipment Cost Comparison ($ X 1000)
Single Use Conventional
Process Equipment 3,900 6,800
Process Utility 1,200 2,200
Process Piping 1,000 2,600
Instrumentation & Control 800 1,800
Electrical 900 1,300
Insulation & Painting 350 600
Taxes, Frieght & Erection 500 1,100
Total Installed Equipment 8,650 16,400
Savings 47.2%

56. Total Installed Costs ($ X 1000)
Single Use Conventional
Total Installed Equipment Cost 8,650 16,840
Building Costs 8,120 18,000
Indirect Costs 4,400 8,500
Commissioning Costs 312 540
Validation Costs 430 1,100
Total Installed Cost 21,912 44,540
Savings 50.8%

57. Capital Breakdown
40,000
35,000
Validation
30,000
Indirect Cost
25,000
Building Cost
20,000 Process Installation
15,000
10,000
5,000
0
Single Use Conventional

58. Space Utilization: Conventional vs. Single-Use
Conventional Single-Use
Common Cell
Common
Cell Culture 8% Culture
18%
33% 20%
Sol.Prep.
33%
Purif.
Sol / GW 33% Purif.
16% 39%
Con SU
SF SF Illustration of Relative Distribution of Net Square
Cell Culture 1600 1200 Feet of Production Areas.
Purif. 3000 2400
Sol / GW 1400 2000
Common 3000 500
Common includes Gowning, Airlocks, and
9000 6100 Controlled Corridors

59. Conclusion - Case Study 2:
• NO CIP systems
• Reduced number of autoclaves to the minimum
• Reduced size of WFI generation by 80%
• Reduced size of clean steam generation by 80%
• Reduced size of compressed air system by 70%
• Reduced size of facility chilled water system by 70%
• Reduced liquid waste generation by 80%

60. In Conclusion - How does Single-Use
Equipment Achieve these Savings?
• Enables Purchased, Disposable, Closed Processing
Systems which…
• Simplifies process operations to save on labor costs
and…
• Eliminates the need to disassemble, clean, and
reassemble complex process equipment in a classified
clean room environment which…
• Shifts the facility design toward fewer expensive clean
rooms and less physical segregation which…
• Allows for more efficient use of facility space and
• Maximizes speed and flexibility for setting up new
process operations.

61. Benefits Summary
• Improved Safety through:
– Better ergonomics
– Lower Process Temperatures (No Steam) & Operating Pressures (Tubing
Pumps)
• Regulatory Compliance enhanced with Closed Processing and Aseptic
Connection technology
• Reduced Suite Space & Mechanical Complexity:
– Fewer Rooms with reduced Clean room Classifications & environmental
monitoring
• Excellent compatibility (leachables & extractables) with various biological
solutions
• Process Operations Flexibility: No Fixed-in-place equipment
• Shorter Set-up time:
– Bag Change = Minutes vs. Vessel CIP/SIP = Hours

62. Conclusions
• Timelines do change
– Less time between batches
– Fill rates can increase, small tubing size, low
pump rates
• Utilities will be affected
– Less WFI, Clean Steam, Process Waste
– Fewer CIP systems
• Design complexity will be reduced
• Capital Cost will be reduced

63. Acknowledgement - Sources of Photos
• Stedim • Genentech
• Hyclone • Acambis
• GE • Wyeth
• Pall • Amgen
• Xcellerex • HGS
• Centritech • EMD
• Lonza • Tyco
• Parkedale Mallinckrodt
• SAIC • DSM Biologics
• Sebra • Medarex
• CPT • Terumo
• Bioprocess Int’l

64. The End