Presented at DCVMN 15th Annual General Meeting, 27-October-2014 to 29-October-2014. New Delhi, India. The presentation can be downloaded from the following site. http://www.dcvmn.org/sites/default/private_files/files/Strategic%20Considerations%20for%20Implementing%20of%20SU%20(Pattnaik).pdf

1. Strategic Considerations for Implementing
Single-Use Technologies in Vaccine Process
Priyabrata Pattnaik, PhD
Director – Worldwide Vaccine Initiative

2. Agenda
DCVMN Annual Meeting, New Delhi | 27 October 20142
What is single use system1
2 Why single use is increasingly being used in manufacturing
When to implement single use3
4 Where to implement single use
How to implement single use5
6 Case study – Cell culture media preparation
Case study – Vaccine formulation7
8 Summary

3. What is a single use system?
Single use system is an engineered process equipment solution, most
commonly assembled from components made using polymeric materials,
which together creates a system or unit operation designed for one time or
campaign use.
Single use components are individual parts designed to perform a particular
function when assembled into a SU system.
Single use assemblies are self contained & pre-assembled plastic fluid
paths, usually provided gamma irradiated & ready to use that uses a
combination of standard components. Single-use assemblies can be
customized to meet defined application.
Example: Fluid transfer containers, Filling system, Sampling bag set-up for QC testing
DCVMN Annual Meeting, New Delhi | 27 October 20143

4. What people have been calling single use….
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5. What people have been calling single use….
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6. Main Feed
w/o L-Tyr & L-Cys
pH 5-6
What people have been calling single use….
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7. What people have been calling single use….
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8. DCVMN Annual Meeting, New Delhi | 27 October 20148
Anatomy of an single use System
Source: PDA Technical Report No. 66, (TR 66)
Application of Single-Use Systems in Pharmaceutical Manufacturing

9. SU components, assemblies and systems
SingleUseComponents
SingleUseSystems
SingleUseAssemblies
DCVMN Annual Meeting, New Delhi | 27 October 20149

10. Reasons for increasing use of SU
components
DCVMN Annual Meeting, New Delhi | 27 October 201410 Source: 9th Annual Report and Survey of Biopharmaceutical Manufacturing
BioPlan Associates, Inc., April 2012

11. Reasons for increasing use of SU
components
DCVMN Annual Meeting, New Delhi | 27 October 201411 Source: 9th Annual Report and Survey of Biopharmaceutical Manufacturing
BioPlan Associates, Inc., April 2012
Not very
relevant
to Vaccine

12. When to implement single use?
12

13. Key decision areas for single use
manufacturing strategies
DCVMN Annual Meeting, New Delhi | 27 October 201413 Source: PDA Technical Report No. 66, (TR 66)
Application of Single-Use Systems in Pharmaceutical Manufacturing

14. Assessment parameters and attributes
DCVMN Annual Meeting, New Delhi | 27 October 201414
• Size, pressure, temperature
limitation
• Complexity of the system
• Compatibility
Is SUS technically
feasible?
• Flexibility
• Facility utilization
• Balance of capital and operating
cost
Business Case
Acceptable?
• Cross contamination
• Adsorption
• Extractable/Leachables
Product Risk
Acceptable?
Adopted from PDA Technical Report No. 66, (TR 66)

15. Assessment parameters and attributes
DCVMN Annual Meeting, New Delhi | 27 October 201415
• System integrity loss
• Process adjustments
• Operator safety
Process risk
acceptable?
• Process validation
• Measurement quality
• Process interaction
Process control
strategy acceptable?
• Regulatory acceptance
• System reliability
• Internal change acceptance
Implementation
strategy acceptable?
• Supply
• Qualification
• Transportation
Logistic control
strategy acceptable?
Adopted from PDA Technical Report No. 66, (TR 66)

16. When to implement single use?
DCVMN Annual Meeting, New Delhi | 27 October 201416 Source: PDA Technical Report No. 66, (TR 66)
Application of Single-Use Systems in Pharmaceutical Manufacturing
Attributes / parameters should be mapped and documented
before the system is designed

17. Risk level vs Process steps
Risk Level – 1
Extractable leachable evaluation
based on extractables data
Risk Level – 2
Additional testing
case-by-case
Risk Level – 3
Product and Process
Specific testing
Buffer
Media Prep
UF – DF
Clarification
Product Mixing
Freeze Thaw
Cell culture
Finish Fill
Product storage
IncreasingRisk
Safety Risk
Regulatory Risk
Testing Efforts
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18. Where to use SUS ?
Risk complexity and applications
DCVMN Annual Meeting, New Delhi | 27 October 201418 Source: PDA Technical Report No. 66, (TR 66)
Application of Single-Use Systems in Pharmaceutical Manufacturing

19. Generic vaccine process:
Where to use single use?
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Finish Fill
Media
Preparation
Risk
Level 1
Risk
Level 3

20. How to implementation single use: A road map
DCVMN Annual Meeting, New Delhi | 27 October 201420 Source: PDA Technical Report No. 66, (TR 66)
Application of Single-Use Systems in Pharmaceutical Manufacturing

21. Implementation of SUS and assessment of
vaccine process and product risk
DCVMN Annual Meeting, New Delhi | 27 October 201421 Source: PDA Technical Report No. 66, (TR 66)
Application of Single-Use Systems in Pharmaceutical Manufacturing

22. Case Study:
Cell culture media preparation
22

23. Generic vaccine process:
Cell culture media preparation step
DCVMN Annual Meeting, New Delhi | 27 October 201423
Finish Fill
Media
Preparation

24. Technical feasibility
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25. Technical feasibility:
What parameters relevant to mixing?
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26. Media preparation in SU mixer
Technical feasibility
 Granulated Trypticase Soy Broth (TSB),
DMEM-F12
 Evaluation Criteria
– Floating solids
– Solubility limits
– Foaming
– Homogeneity determination
 Mixing strategies
– Maximize power to volume ratio
• Dispense solute into MIX containing the
minimum working volume of solvent
– Run the impeller at high speed
• Creates a vortex to draw floating solids down to
the impeller
• Higher shear and turbulence at the impeller
– Use elevated temperature to promote faster
dissolution
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27. Mixing studies in single use mixer
 Develop mixing conditions and times
 Couple with filter sizing/pilot studies
Media filtration optimization
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28. Process risk considerations
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29. Process risk considerations
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All points
relevant
to Vaccine
processes

30. Product risk considerations
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31. Product risk considerations
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Less likely a concern for media preparation in SU

32. Summary
 Media Preparation falls under risk level 1
 Single use has been successfully used and implemented for
media prep and storage applications
 The risks have been assessed by different manufacturers and
found to be generally acceptable and manageable
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33. Case Study:
Multivalent vaccine formulation
33

34. Generic vaccine process:
Formulation and fill finish step
DCVMN Annual Meeting, New Delhi | 27 October 201434
Finish Fill
Media
Preparation

35. Risk profile of SUS items
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36. DCVMN Annual Meeting, New Delhi | 27 October 201436
Vaccine formulation and bulk preparation
Process involves mixing, storage, and
transfer of products for filling

37. Flow diagram of single-use formulation of
multivalent vaccine in a closed system
DCVMN Annual Meeting, New Delhi | 27 October 201437 Source: Tony D’Amore and Yan-ping Yang (Sanofi Pasteur)
BioPharma Asia, July/August 2013, pp. 8-19

38. DCVMN Annual Meeting, New Delhi | 27 October 201438
Layout of a typical single-use finish & fill set-up for
vaccine applications
Capping
Crimping
100% vial washing
inspection

39. Assessment of vaccine process and product
risk is more critical for formulation and fill
DCVMN Annual Meeting, New Delhi | 27 October 201439 Source: PDA Technical Report No. 66, (TR 66)
Application of Single-Use Systems in Pharmaceutical Manufacturing

40. Assessment of vaccine process and product
risk is more critical for formulation and fill
DCVMN Annual Meeting, New Delhi | 27 October 201440 Source: PDA Technical Report No. 66, (TR 66)
Application of Single-Use Systems in Pharmaceutical Manufacturing
All the points under
- Technical feasibility
- Product risk considerations
- Process risk considerations
are critical for formulation and fill operation

41. Why to implement single use in formulation
fill application, when the risks are higher?
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42.  Single use expendable cost
Economic Benefits
Product/Process Security
Speed to Market
Direct (Variable Costs) Indirect (Fixed Costs)
Assessing Potential Economic Advantage
of Single-use Technologies
 Reduced Utilities
 Validation/Revalidation
 Technology adoption
 Throw away cost
Capital Investment
Stainless steel
Autoclaves
Facility “foot print”
Utility service
Capacity
Turn round time
 Reducing “bottlenecks”
Multi product flexibility
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43. Cost advantage of SUS in formulation fill of
vaccines
14 HrsClean and set-up
Cleaning validation
Filling time
Average vials/hr
<1 Hr
Extensive Zero
24 hrs 10 hrs
3,000 10,000
50 0Aseptic connections
Traditional SU Solution
36 Hrs 12 Hrs
Operator Training 2 weeks 2 days
Equipment utilization 35% 82%
CAMPAIGN FILL TIME
43 Source: Jenness E, Gupta V (2011) Implementing a Single-Use Solution for Fill–Finish
Manufacturing Operations, BioProcess International Supplement, May 2011: 22-26.
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44. Summary
 Formulation and fill operations falls under risk level 3
 Single use has been successfully used and implemented for formulation
and finish fill applications
 The risks have been assessed by different manufacturers and found to
be acceptable due to significant operational cost advantage
 Risks are manageable by careful planning and implementation
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45. Take home message
 Single use implementation in vaccine production is a strategic
consideration that needs deeper level planning and analysis
 Use of single use technologies can quickly help increase operational
flexibility and manufacturing capacity
 Implementation of single use technologies is a multi-stage collaborative
process
 Contact Merck Millipore to further discuss and learn about the subject in
details
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