1. Marcelo Anderson Manufacturing Sciences Biogen
Changing the Paradigm:  How Biogen tech transfers processes into our disposable manufacturing facility
Marcelo Anderson
Manufacturing Sciences
Biogen

2. Streamlined Processes
Agenda
Technology Transfer Defined
Scope & Thesis
Technology
Business Processes
Technology Transfer
Possible Next Steps
Questions
Disposable Equipment
Flexible Facility
Understand Your Asset
Facility Scheduling
Team Structure
Streamlined Processes
Agenda – Focus on Tech transfer
Simplify
Information
Decision Making

3. Process Technology Transfer
Transfer all the knowledge needed to perform a given biotech process from a Transferring Site to a Receiving Site
ISPE 10 September 2009, Herwig Kapeller, Novartis Pharmaceuticals Corp.
Also includes - Responsible for the successful production, disposition, stability and product comparability from transferring site to receiving site.
Biogen Global Technology Transfer
Definition and additional inclusion

4. Scope & Thesis
Scope – early clinical (FIH/I/II) production of recombinant biotherapeutics with mammalian cells
Thesis – the right technology+ business systems+ Tech Transfer allows for transformational performance -> >75% improvement
The System brings transformation. Everyone loves technology so let’s talk about that first

5. Technologies: Strategy
Fully compliant for phase
Keep it simple
Keep it flexible
Make equipment identical to pilot plant
Innovate – within and piloting
Make it differentiated
Capability
Capacity 5

6. Technologies: Applied
Disposable Equipment
Disposable
Adaptable - on and off platform
Closed
Flexible Facility
Stand alone
Small footprint
Innovation space
Clinical: Pre FIH, Phases 1 to 2
Understand Your Asset
Understand advantages
Differentiate
Innovate

7. Understand Your Asset FVM vs SSM (Titer – 4 g/L)
Breakeven point ~ 8 kg
Cost and duration advantage at smaller material demands. Driven mostly by scale difference. System must leverage strength to create value. Value attributes specialize out system for FIH and phase 2 only. Therefore we have technologies that have give us a speed and cost advantage. Fail fast and fail cheap.

8. Low pH Viral Inactivation
Disposable Equipment
1,000L
Detergent
Viral Inactivation
Low pH Viral Inactivation
Disposible equipment- what does that mean? How many people have worked with disposible systems before? Flasks, wave bags and bioreactors seems obvious. We also do filtration for clarification, disposible columns and UF and finally bags. Aseptic connections are utilized to connect equipment and cleave off the previous unit operation. When done with a process there is no cleaning, everything is thrown away. Therefore facility change over time is brought down to hours and pre-use equipment cleaning expiry is measured in months. Equipment provide a mechanism to think about process differently.
A.Shukla et Al (2012), Vertical Integration of Disposables in Biopharmaceutical Drug Substance Manufacturing. BioProcess International 10(6)

9. Flexible Facility (FVM)
10,000 square foot facility in RTP utilizing upstream and downstream single-use technologies
Closed process from inoculum prep through final drug substance bagging.
Approach designed for speed and adaptability which enable transformational improvement
Facility design allow for separation of upstream and downstream stream to facilitate concurrent production. Not unusual to have 3 or 4 batches in various stages.
Four clinical campaigns completed successfully demonstrating proof of concept
ISPE Facility of the Year Award 2013

10. Business System: Strategy
Development Pilot Plant ?
FVM
Commercial cGMP
FVM
Change Control Rigidity
Tox Material
Traditional SS Clinical
Fully compliant
Keep it simple
Use original sources of data
Innovate
Team structure and strategies used are independent of the FVM operation (can be applied elsewhere).
Ask that FVM be used as a pilot area for testing concepts before deploying elsewhere within organization
- In order to continue to build systems that focus on rapid production start / quick release
- FVM current focus is on team design for fulfilling needs of a small production environment
-Technically strong staffing – not the typical group of MA’s: engineers, scientists, seasoned mfg. staff (high level)
Proximity is undervalued – put people with the right level of expertise/responsibility in a room and things get done (versus the never ending string of s)
Short Term:
What to do during downtime?
Some staff rotational
Who reports to who?
An empowered IOU breeds innovation – gives it that start-up feel 10

11. Business Systems: Applied
Facility Approach and Scheduling
Adaptability/$ to failure
On demand production
Organized like pilot plant
Team Structure
Self directed team & independent
Commitment/expertise on the floor
Increases equipment flexibility
Streamlined Processes
Standard document templates
Alignment between groups
Optimized tech transfers

12. FVM Facility Thought Process and Scheduling
Industry Standard: Approximate Timeline from Cell Line Selection to IND: months Q1 Q2 Q3 Q4 Q5 Q6
Non-GMP
Process Development
Tox-pilot
Tox Study + FIH Protocol
R to D Transition
F/R
GMP
Raw Material Procurement/ TT
Bulk Mfg
DP Fill
Pack / Release
DS Release
DP Release
IMPD’s
Stability
IND Filing
FVM Thinking: Approximate Timeline from Cell Line Selection to IND: 10 months Q1 Q2 Q3 Q4 Q5 Q6
Process Dev
Non-GMP
FIH Protocol
Bulk Mfg
Bulk Mfg
RM Procurement
DP Fill
DP Fill
DS / DP Release
DS / DP Release
GMP
Pack / Release
Pack / Release
Tox Study
Stability
IND Filing
IMPD’s

13. Rapid Supply of Clinical Material
FVM Team Structure -Integrated Operations Unit (IOU)
Common Goal
Rapid Supply of Clinical Material
Leadership
Drive Vision
Develop Business
Quality
Compliance
QA Sys.
Systems
Documentation
Knowledge Management
Operations
Production
Concept Deployment
Planning
Schedule
Inventory
Technical
Process Expertise
Single Use Sys.
All members co-located on the production floor
Diverse skillset
Senior Mfg. Associates
Engineers
Scientists
Junior staff with high potential
Team is empowered to make decisions / create new business processes
Team structure and strategies used are independent of the FVM operation (can be applied elsewhere).
Ask that FVM be used as a pilot area for testing concepts before deploying elsewhere within organization
- In order to continue to build systems that focus on rapid production start / quick release
- FVM current focus is on team design for fulfilling needs of a small production environment
-Technically strong staffing – not the typical group of MA’s: engineers, scientists, seasoned mfg. staff (high level)
Proximity is undervalued – put people with the right level of expertise/responsibility in a room and things get done (versus the never ending string of s)
Short Term:
What to do during downtime?
Some staff rotational
Who reports to who?
An empowered IOU breeds innovation – gives it that start-up feel
Rotation
RTP MFG
On the Floor 13

14. Team Structure - Applied
On-the-floor Issuance
Local Inventory
Real-Time Transactions
BPR
Review
Production
Hours
Real World Examples – Not Staged
Tech (MS)
Systems (Doc)
MFG
Ex. BPR Issuance & Review
Rotation
MFG MS TD
Ex. Brx Inoculation & BPR Review QA
Leverage work that has been done in FVM in conjunction with ongoing efforts on self-directed teams. Team structure and strategies used are independent of the FVM operation (can be applied elsewhere).
Ask that FVM be used as a pilot area for testing concepts before deploying elsewhere within organization

15. Tech Transfer Process: Strategy
FROM TO
Conventional tech transfer
Seamless knowledge transfer
“Line function centric” approach
Nimble “product centric” approach
Multiple hand-offs
Minimal hand-offs
Application of commercial- centric systems for all
programs
Adopting flexible/simplified system for clinical programs
a new operating model, where an accelerated approach for early phase drug development is realized. Our clinical supply chain is optimized so that cGMP compliance lives comfortably alongside the flexibility required to enable rapid delivery of clinical supplies.
It is a model that dissolves the existing functional operating boundaries in the transition of clinical programs. Success means, every individual’s contribution increases the opportunity to advance more drug candidates.
From “Clinical Supply Transformation New Business Model” September 2011
Kasra Kasraian, Rhonda Sundberg, Steven Doares, Adam Sheriff, Tom Holmes, Ian Rosenblum, Rick Shansky, Andre Walker 15

16. Tech Transfer: Applied
Simplify
Focus on the critical / eliminate unnecessary
Minimize membership
Same equipment throughout
Information
Centralized information done once
Automatic record creation
Information ownership clarity & empowerment
Decision Making
Reframing Risk
Transfer decisions / ownership
Team of 4

17. Simplify Traditional Transfer FVM Transfer 3L only
Characterize platform & Process screening
Lab work to manage differences
Confirm at pilot & full scale
Ensure comparability
Rapid deployment
Minimize risk to ensure schedule
Product stability + phase 1/2 material
Typical transfer 12+ months & >$2.5MM
Team – dozen+
3L only
Take the risk
FVM is full scale
Nothing to compare to
Minimize deployment
Schedule adjust to success
+Tox
4 weeks & $50K
Team - 4

18. Batch Production Record
Information
Batch Production Record
PFD
Record
Unit Op Instruction
Materials Table
Clinical Comments
PFD Development
PFD Approval
Process Description
Record Development
Record Approval
Record Issuance
Revision Cycle
Source for operational parameters
Empowers staff with process knowledge
Modular, semi-chronological form
Serves as activity log
Flexibility for real-time change
Template batch records decouple process description from operational instruction
Minimizes resource burden responsible for documentation development
Minimizes timelines (non-iterative development & independent review process)
Template batch records adapt to unpredictably of an early clinical processes
Provide increased flexibility at expense of being less prescriptive
Requires knowledgeable staff to execute (ex. normalized values) 18

19. Decision Making Empowered team of 4 Notes Representation
Similar to development
Notes
Communication ease
Empowered for decisions
Readies team for decisions
Need right personalities
Stainless:
FVM Single Use Systems:
Manual Systems – Low configuration 19

20. Streamlined Processes
Summary
Simplify
Information
Decision Making
Facility Scheduling
Team Structure
Streamlined Processes
Disposable Equipment
Flexible Facility
Understand Your Asset

21. Possible Next Steps Velocity Scheduling Simplicity
R to MFG, no passing D
6 month supply chain - +DP/LP
Throughput - Multiple purification areas
Disposable continuous chromatography
Scheduling
On-demand
Disposable buffer concentrates
Simplicity
Replace depth filtration
60cm disposable column

22. Acknowledgements Rich Guerra Mark Chen Shane McCarroll Chad Cooper
Matt Haines
Chris Antoniou
Jack Kane
Venkatesh Natarajan
Scott Keetch
Matt Westoby
Phil Vilmorin
Devin McCann
Diana Brown
Mike Rogers
Lynn Conley
Sanaa Elouafiq