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

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

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

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

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

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

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.

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)

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

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 emails) 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

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

FVM Facility Thought Process and Scheduling Industry Standard: Approximate Timeline from Cell Line Selection to IND: 18-24 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

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 emails) 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

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

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

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

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

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

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 http://teams/sites/FVM 19

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

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

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