Facility Establishment Time and Cost Effective

1
Facility Establishment Time and Cost Effective
2008 PDA/EBE Conference on
Biopharmaceutical Development and Manufacturing
24-25 June, Dublin, Ireland
Morten Munk, VP CMC Biologics A/S
2
(No Transcript)
3
Outline

• Timelines for designing and building new
  facilities
• Conceptual design, modularization 3D design
• Case study CMC Biopharmaceuticals A/S

4
Challenges Time, risk and cost

• Products must be launched as fast as possible
• Reduce total project schedule, risk and cost
• Confirm market potential before capacity
  expansions

RD process
Clinic I
Clinic II
Clinic III
Approval
Production
Pilot Plant
Launch Plant
Commercial production
Construction/IQ/OQ
Design
PQ/PV
Time squeeze
5
Parallel execution

• Major time savings
• Being able to construct the buildings and the
  equipment (as modules) at the same time on
  different locations

Traditional
Building
Equipment
Modular
Install.
Building
Equipment
Intro
Demand
Capacity
Costs
Sum.
6
Time Cost estimate
Year 1
Year 2
Year 3
Year 2
Year 4
Q1
Q3
Q2
Q4
Q3
Q4
Q1
Q3
Q2
Q4
Q1
Q3
Q2
Q4
Q1
Q2
CD
BD
Detailed Design, Process Building
Building Construction
Production of Process Equipment
Vali- dation
Appro val
Installation Qualification
Production
Cash Flow
7
Impact of Decision Time
24 Month Project 90 chance of being needed
Shorter project period significantly reduces
project risk
Adapted from Bovi Lend Lease Why still batch
operations ISPE Amsterdam 2007
8
Increasing upstream yields and single use
technology change biotech production paradigm
Traditional yields 10.000L SS 6-pack
Increased yields (5 times) 2000L Single Use
6-pack
9
Why is Conceptual Design important?
The early Decisions have most Impact on the
Investment
of Total Project Investment
10
Concept Development
Capacity analysis
Process Modules
Flows, logistics, Automation etc.
Operations flow diagram
Area needs
11
Modular Engineering
starts in the
Conceptual Design Phase
CD
12
Fast approach with minimized risk

• An alternative approach is to break the project
  into a structure of de-coupled, physical,
  functional modules

• Which can be handled in parallel throughout the
  project
• For which concepts for all major project
  activities can be established and then repeated
  module by module
• Which can be used for a high resolution project
  control
• Keywords being Structure, Parallelism,
  Concepts, Project control

Intro
Demand
Capacity
Costs
Sum.
13
Distribution piping
Second generation Erection off site

• First generation
• Erection on site

Intro
Demand
Capacity
Costs
Sum.
14
Facility Trends Flexibility

• Reduced batch size
• Multi- not single product capability
• Campaign based processing
• Flexibility and adaptability by design
• Increased use of disposable technology

• More specific indications
• Orphan drugs
• Increased yields
• Increased potency
• Shorter product life cycles
• Pressure to reduce cost
• Increased use of outsourcing

15

A Centre Of Bio-manufacturing Excellence In
Europe Purpose Built For Contract Manufacturing
CMC case study
16
DNA to API Pre-tox to CommercialRegulatory
Compliance
ChemistryManufacturing Control
Biopharmaceuticals based on MAMMALIAN CELL
CULTURE MICROBIAL FERMENTATION
17
CMCs Manufacturing Facilities
Copenhagen facility

• 2 x 750L w/v GMP Cell Culture Line
• 350L w/v GMP Cell Culture Line
• 100L w/v GMP Cell Culture Line
• 100L w/v Cell Culture Pilot Plant
• 2 x 1,750L w/v GMP Microbial Line
• 100L w/v Microbial Pilot Plant

• Process Development Laboratories
• Analytical Development QC Laboratories
• Cell Banking

18
Copenhagen Facility Floor Plan
19
3D Process visualization
20
3D Process visualization
21
Manufacture in CMC Cell Culture Line I
Purification II
Purification I
Cold room
Cell Culture Suite
Recovery
Cell expansion Suite
Only Cell Culture bioreactors and large recovery
tanks are stationary
22
Process Overview
Cell Culture Suite
Purification II
Purification I
Cold room
Recovery
UF
500L
500L
500L
500L
500L
Protein A
500L
500L
750L Bioreactor
500L
1000L
500L
1000L
100L Bioreactor
500L
15L Bioreactor
Cell expansion Suite
Shakers
23
(No Transcript)
24
Gladsaxe FacilityEarly December 2002
Preparing for the first Christmas party in the
new facility
25
CMC Facility Timelines

• April 2002 Contract signed for the new facility
• August 2002 Ground breaking
• December 2002 CMC Christmas party in the
  basement
• December 2003 CMC moves into the new facility
• April 2004 First GMP production
• June 2004 DMA authorization for clinical supply
• December 2004 Completion of qualification
  activities
• June 2005 DMA authorization extented to
  commercial supply
• June 2008 30 Customer projects
• 20 months from ground breaking to first GMP
  production

26
Health Authorities Inspection History

• June 2003
• Danish Medicines Agency (on behalf of EMEA)
• Symbion Science Park, approval for Phase I II
• June 2004
• Danish Medicines Agency (on behalf of EMEA)
• Copenhagen Facility, approval for Phase I, II,
  III
• June 2005
• Danish Medicines Agency (on behalf of EMEA)
• Copenhagen Facility, approval for Commercial
  Phase I, II, III
• Januar 2008
• Danish Medicines Agency (on behalf of EMEA)
• Additional audits by
• Ex-FDA consulting company KMI Parexel
• Numerous companies

• USA
• Ex-FDA senior inspectors assessment of the CMC
  Quality System facility The review revealed
  CMC to be operating in a modern, state of the art
  manufacturing facility suitable for production of
  biological APIs. The risk of this site failing
  an FDA systems based inspection was determined to
  be very low.

27
Learnings from building project

• Choose engineers and contractors with a relevant
  and good track record
• Identify the key persons assigned at the
  Engineering Contractors
• Know your contract and your design
• Allocate sufficient resources for User
  Requirement Specification gt minimize changes
  when the construction is started
• Allocate internal resources can be difficult
• Early involvement of key users with decision
  power
• During CD define and work with flow of
  Personnel, Product, Waste, Raw Materials, Ect.

28
Learnings, continued

• Define milestones and act on delays
• Be prepared to re-negotiate terms, design and
  timelines
• Allow for building inaccuracies in your 3D
  design
• Define fix points in the building for your 3D
  model
• In general, expect problems and plan ahead
• Be involved - It is your timelines and your cost!

29
Acknowledgements

• Thanks to
• Niels Guldager, NNE Pharmaplan
• Providing information on latest trends in the
  market
• Selected NNE Pharmaplan slides

30

• Morten Munk,
• CMC Biologics A/S
• MM_at_cmcbio.com www.cmcbio.com