The document outlines key considerations for building a cGMP biomanufacturing facility, emphasizing the importance of flexibility, process design, and regulatory compliance. It discusses the market trends in biomanufacturing, the design and engineering requirements, and the benefits of single-use technologies over traditional methods. Additionally, it highlights the project's planning phases and the need for a robust project management approach to ensure operational efficiency and cost-effectiveness.

1. BioReliance® End-to-End Solutions
Key Considerations & Case Study
for Building a cGMP Biomanufacturing Facility
A Molecule’s Journey

2. 2
The life science business of
Merck KGaA, Darmstadt, Germany
operates as MilliporeSigma
in the U.S. and Canada.

3. • Governments developing self
sufficiency programs for
local production of biologics
• Local biosimilars with
lower costs starting to
cannibalise originator
biologics
• Global Big Pharma
producing in local
emerging markets
• Developing
economies
spending €billions
on medicines
importation
• By 2020, prescription sales
expected to top €1tn globally
Market Trends in our Industry
3

4. 4
Pre-clinical Phase I Phase II Phase III Commercial
Early stage offering:
Cell line development
Upstream / Downstream process dev
Analytical development
GMP Clinical supply
Late stage offering:
Process validation
Analytical methods validation
Process scale up
Facility design, Equipment supply, GMP training
Tech transfer
We are the process development and manufacturing partner
for developers of innovative medicines, accelerating their time
to market

5. 5
We are the process development and manufacturing partner
for developers of innovative medicines, accelerating their time
to market

6. Advanced Biodevelopment Centers
Burlington,
MA, USA
E2E PD Labs... up to GMP 4KL capacity
Martillac, France
GMP 2KL
Shanghai,
China
6
• 250 employees
• About 8000 m2
• Global GMP capacity of
5,000L immediately
upgradable to 9,000L
• Built in 1987 for discovery
to manufacturing scale of
proteins
• Experience with over 230
proteins - antibodies,
hormones, fusion proteins

7. Our Clients
30%
55%
10%
5%80% Ph. I, 20% Ph. II/III
15% BIOSIMS, 85% NBEs

8. Transfer to
any facility, any scale
End-To-End Solutions - Greater flexibility for manufacturing
8

9. • Investing quickly to be the first to enter the market
• Lowering project financial risks
• Ensuring drug products COGS are competitive and affordable
• Smaller scale processes in multiproduct plants
• Higher process flexibility for better facility and capacity utilization
• Processes and facilities clonability/repurposability
The Challenge for our Industry
9

11. 11
Facility Design – Fully Single Use

12. 12
Facility Design Hybrid

13. USP 2 USP 1 USP 2
New USP 3
Storage
warehouse
USP 1
Existing
configuration
New configuration
Construction or revamping?
13

14. Upstream suite design
• Dimension: 87 m² / Height 4m90
• Designed to fit 2 x 2000 L bioreactor
• Seed train
• Clarification
• Media prep/Harvest storage (temperature hold)
Small amplification room
• Dimension: 11.6 m² / Height 2.5 m
• Hood, incubators
Class D
Controled unclassified suite
Technical Area
Building Revamping
Upstream suite layout
14

15. Week 0 Week 2 Week 4
Week 5
Week 8
Building Revamping
15

17. 17
− Fit To Strategy: the Biomanufacturing facility goals must be defined
− Type of molecule: small / large, Potent or not, …
− Multi products
− Multi phases
− Volumes to produce, ramp-up
− Location
− Fit To Process: the most appropriate technologies must be defined
− Existing process? Filed? New template?
− Expected Yield and Titer
− Level of Flexibility?
− SUT, Hybrid, SS?
Engineering considerations

18. 18
− From the early stage of the project, implement a good project
management and create the right project team with the right
competencies: Process, Operations, Quality, EHS, Engineering
− Define the Quality & HSE and Engineering frame: Which regulations
are applied to the project?
− Set-up a masterplanning for the project with the right duration for the
different phases: Design / Construction / Qualification & Validation / start-
up.
Project considerations

19. 19
− From Process to Facility Design: The foremost consideration is
prevention of cross contamination
− Flexibility, Agility, Operational Efficiency and Cost Effectiveness are the key
drivers in the design of a Biomanufacturing facility. Enablers the team
must focus on during the conceptual design phase of the facility are:
− Process architecture
− Segregation concept of the process area
− Support functions and connections with the process suite
− Personnel, Product, Waste, RM Flows
Design considerations

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A right design of a biomanufacturing facility should ensure that:
− The space dedicated for the operations is properly sized
− When several suites are considered, define the gowning and airlock
concepts in order to manage multi products & multi phases.
− The flows are adequate to prevent mix-up and cross contamination
− The entrance of materials and personnel is limited in the process
area
− The facility is agile by designing suites that can be rapidly
reconfigurable: Size, ceiling clearance, access, HVAC, position of utilities
panel, drains
− The facility is designed to accomodate future regulatory or technical
changes without major shutdown
Design considerations

21. 21
− Location of the facility
− Retrofit, expand an existing site or greenfield
− Type of clean rooms: Stickbuilt construction, modular panel or
prefabricated room >> do we need to relocate? Repurpusable facility?
− Turnkey or classical engineering approach
Building considerations

22. Martillac site: Flexibility and Speed are Key!
Rapid suite configuration for
a variety of processes
Rapid changeovers
between batches
Closed processes
Sterile pre-assembled
disposable assemblies
sterile connectors /
tube welders
Process Flexibility
Reduction of
Contamination
Risks
Ease of
Use
Lower CapEx
Facility / Equipment
Lower OpEx
Process!
22

23. Single-use vs. Stainless Steel – Time & Cost Savings
Comparing our Biodevelopment Center USP suites: Single-Use vs. Stainless Steel
RUN
RUN
Preparation / Parameter setting
Media conditioning
CIP/Requalification/Maint.
Preparation
Preparation
USP1 : 1250L Stainless Steel Bioreactor
USP2 & 3: 200L / 2000L Single-Use Bioreactor
RUN
Traditional Single -
use
Time Spent to perform
qualification (IQ/OQ/PQ)
5 months 1 month
Time Spent to prepare the
bioreactor (Assembling
Sterilization, cleaning) /
bioreactor
2 -3 days 2-3 hours
Preparation
23

24. - Early integration of manufacturing constraints in
Development (Equipment, Titer, Volume, RM)
- Processes mapping and optimization (« closed », USP
intensification, Process Analytical Technologies…)
- Capacity increase but with a critical liquid flow
management (concentrated solutions with inline dilution)
- Good supply management with Kanban for consumables
- Low volumes of chemicals, less handling risks
1.
Process
Key Elements of Focus: When The Transition to SUT is Initiated
24

25. 2.
Facility/
Utilities
- Pharmaceutical areas are less complex (not hard-piped, CIP,
SIP…) with optimized footprints, repurposable work areas
- Closed systems allow for a decrease in environment controls
- Reduction of energy type & consumption level
- Standardization of equipment and associated PM (risk
analysis, service consolidation). Less overall complexity.
- Pre-engineered solutions can be used to accelerate the
availability of desired capabilities
Key Elements of Focus: When The Transition to SUT is Initiated
25

26. 3.
Engineering
- Master Plan availablity (expansion)
- URS availability with a clear definition of the
needs/specifications (capacity, purpose (CT/Commercial,
mono/multi products, batch/campaign…)
- Early Integration of local requirements (QA, EHS…)
- Optimize the workflows (personnel, bioproduct &
media/buffers, waste materials…). Experience the
scenarios with future users of facility
- Integrate staging/storage areas
- Consider Automation/Supervision and 21CFR Part11
compliance impact
Key Elements of Focus: When The Transition to SUT is Initiated
26

27. Once the equipment has been selected, it is placed in the facility
1.To meet all Process, Quality and Regulatory requirements
2.For operator Ease of Use and Accessibility during any required maintenance
General Facility Layout
From the general facility layout, generate specific layouts to experience and check
the faisability
1. Room classification
2. Room pressurization
3. Personnel flow
4. Material flows including raw materials, waste, and final product
Once the Process is Known…
27

28. General Facility Layout
Once the Process is Known…
28

29. 3D Drawings & Tools
Once the Process is Known…
29

30. Your choices
will impact
your success
Location…
• Do you have an existing building?
• Is ‘clonability’ desired for other locations?
• Possibility of relocation?
Drug production forecast…
• Single-product or multi-product plant?
• How to match current production scale?
• Capacity/scalability needs (up and down)
• Possibility to re-purpose facility/eqpt?
Budget…
• How to assess financial impact and gains of different options?
• Cost impact in case of relocation/ repurposing ?
Time…
• Need for rapid deployment?
• Expedited timing/constraints?
To conclude…
30

32. Regulatory Risk Assessment
Fit for
Purpose
Location
Cross-
contamination
32

33. Fit For Purpose
Multiproduct
Expansion
plan
Commercial
Strategy
Type of
product
Type of production
Batch / Continuous
Stainless steel /
Single use
Production Scale
33

34. Location is key
• In which country to file?
• Which regulatory agency will inspect the
facility?
• Which regulation to conform with?
- GMP guidelines
- Widespread guidelines application EU / US
- Harmonized ICH guidelines
- Country specific considerations
34

35. Cross-Contamination prevention
Product flows
Personnel flows
Work areas adapted to internal organization
Risk-mitigation according to activities performed
Microbial / Viral / product cross contamination
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-
-
-
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36. 36

37. The life science business of Merck KGaA, Darmstadt, Germany operates as
MilliporeSigma in the U.S. and Canada.
MilliporeSigma and the vibrant M are trademarks of Merck KGaA,
Darmstadt, Germany. Copyright © 2017 EMD Millipore Corporation. All
Rights Reserved. BioReliance is a registered trademark of Sigma Aldrich Co
LLC. BioReliance is an affiliate of Merck KGaA, Darmstadt, Germany.