ALNYLAM RNAI BIOTECHNOLOGY MANUFACTURING FACILITY AUTOMATION SCOPE DEVELOPMENT

ALNYLAM RNAI BIOTECHNOLOGY MANUFACTURING FACILITY AUTOMATION SCOPE DEVELOPMENT AND INTEGRATOR SELECTION PROCESS Aaron Conant March 13, 2018 ISPE Raleigh, NC ISPE-Ca. SA 2018 Technology Conference

ALNYLAM PHARMACEUTICALS BACKGROUND

Alnylam Pharmaceuticals Company Overview Cambridge-based company pioneering RNAi as a potential new class of innovative medicines • Corporate headquarters in Kendall Square, Cambridge, MA • Development and commercial hub office, Maidenhead, UK • Existing Alewife Manufacturing Facility, Cambridge, MA • New Greenfield Manufacturing Facility, Norton MA • Founded 2002 • Approx. 750 employees world-wide • Targeting rare diseases • h. ATTR Amyloidosis • Acute Hepatic Porphyrias • Hemophilia A & B • Hypercholesterolemia Connecting Pharmaceutical Knowledge ispe. org

Norton, MA Greenfield Facility Overview • Approx. 210 K square feet • 2 manufacturing trains, space for 3 rd • Solvent storage, distribution • Clean and black utilities • Warehouse • QC labs • Majority of plant electrically rated • C 1 D 1 (10%) • C 1 D 2 (70%) • Non-classified (20%) Connecting Pharmaceutical Knowledge ispe. org 4

AUTOMATION STRATEGY CONSOLIDATION OF SYSTEMS, PLATFORM SELECTION

Preference to Segregate Site Into Two Distinct Automation Systems Process Automation System (PAS) Building Automation System (BAS) > Designated as the central system for all GMP data collection, alarming and control. > Designated as the central system for all non-GMP data collection, alarming and control. • Clean Utilities • HVAC • Solvent Handling • Gas Monitoring • Train 1 Process Area • Electrical Monitoring • Train 2 Process Area • Refrigerant Monitoring • Critical Environmental Monitoring and Alarming • Lighting controls • General alarming • GMP response- audit trail and history • Connecting Pharmaceutical First response- trouble notification to Facilities Knowledge ispe. org 6

Segregation Enabled Minimized Qualification Workload Utilized signal isolators to split critical readings (room pressure, temperature, humidity) needed within each system • PAS for GMP monitoring, alarming, trending • BAS for monitoring and control • Sensor, transmitter, and isolator within the GMP boundary • System access allows us to have reduced controls for Facilities and Contract Support • Streamlined documentation and change management Qualification strategy risk-based Segregated design allows us to outsource majority of system ownership and issue response • Minimal internal staff expertise required, oversight role of vendor • Contract will include off-hour response, but set days per week to be onsite to do daily support to provide core System Owner tasks • Segregation allows right-sized controls for BAS • BAS commissioned only • PAS qualified, risk-based approach, ASTM E 2500 • Library Objects considered COTS, validation of only changes • Project Execution and Quality plans govern System Integrator testing, to be leveraged as validation System administration, maintenance, troubleshooting Connecting Pharmaceutical Knowledge ispe. org 7

Process Automation System Selection – Rockwell Automation, Plant PAx Distributed Control System • Plant. PAx ® DCS Hit Right Value/Price Point • Similar capability and functionality within platform for major vendors • Recent advances in centralizing product into DCS • Lower installation and scale up costs • Larger talent pool of skilled System Integrators • Penetration within OEM, skid vendors, easier integration • • Initial Licensing and Annual Maintenance • Consulting Service/Support ($/hr) • Additional system expansion costs • • Configurable to requirements • Secure, proven, robust • Innovative tools and techniques • Total Cost of Ownership • Design/Scalability Operational • Capability within platform (alarming, data collection, graphics, security) • Future “bolt on” capability such as MES, Data Analytics • Reliability and flexibility to maximize system uptime Controllers, workstations, IO Connecting Pharmaceutical Knowledge ispe. org

Building Automation System Selection – Albireo Energy, Delta Controls • • Right-sized product for our use Lifecycle Support Service • HVAC system with central monitoring capability • Experience with project team • No intention to make this a multi-site, dashboard hub for energy management • Competitive support contract • Local support for 24 x 7 response • Design/Scalability • Up to date: current technology • Innovative: unique features • Strong performance at other customer sites • Operational • Simplistic design, majority of issues can be resolved by technician Connecting Pharmaceutical Knowledge ispe. org

Project Details - Infrastructure • Fully virtualized server farm • ACP Thin. Manager as HMI solution • IT-OT Convergence • IT and OT joint partnership in management • Hardened terminals to be ACP enabled “bricks” • Datacenter virtualized infrastructure • Leverage mobility (tablets, smartphones) • • Enhanced content management for increased productivity Smart active directory and domain management • Smart and secured authentication for remote support • Vantage. Point, View. Point applications • Connecting Pharmaceutical Shared Responsibility • IT owns infrastructure and security design • Automation supports applications and control hardware (HMI, PLC) Knowledge ispe. org 10

OEM and System Integration Selection Process • • OEM Plan • • Where possible, specified skid vendor to supply remote IO, no control system Where proprietary “smart” skid, integrate for data collection and monitoring • • System Integrator Selection Investigating direct control integration (serial, OPC) for some skids Specified skidded systems, such as Parts Washer, WFI Generation with standard Allen. Bradley controllers and Panelviews Specified black utilities, chillers and boilers, to have a supervisory front-end within FTView Connecting Pharmaceutical • Key requirements • Strong Project Management tools and techniques • Talented Plant. PAx ® DCS design team, previous experience with innovative solutions • Relevant project experience within Life Sciences industry • Local presence for long-term relationship Interviewed 20+ firms, narrowed to 5 bidders • Knowledge Selected Avid Solutions, Evolve Systems Partnership ispe. org 11

PROCESS AUTOMATION SYSTEM DESIGN AVID SOLUTIONS

System Integrator Overview Avid Solutions • Established in 1987 • Over a Millennia of Automation Experience • 125+ Personnel (4 Locations) • Extensive Upgrade & Migration Experience • CSIA Certified Integrator • 55%+ Business is Life Sciences • Rockwell Automation Solution Provider 1 2 3 Partnered with E-Volve Systems • Established in 2011 • 25+ Personnel • Merrimack, NH & Cincinnati, OH • Extensive Experience in Biopharmaceutical Industry • Rockwell Automation Recognized System Integrator 4 Connecting Pharmaceutical Knowledge ispe. org 13

Detailed Design Elements Overview • • Hardware • • Control Panels • • Software Consolidation of initial design reduced # of panels required Controller Redundancy • • • Upfront study allowed early procurement of licenses • Industrial Data Center purchase enables commissioning flexibility during construction Risk-based analysis reduced costs/complexity • IO Selection • Network Architecture Electrical classification requirements met (C 1 D 2) while standardizing on Control/Compact Logix IO Connecting Pharmaceutical Plant. PAx full suite of applications • • View, Batch, Vantage. Point, View. Point, Asset. Centre Plant. PAx library of process object selected Knowledge ispe. org 14

IO Architecture Connecting Pharmaceutical Knowledge ispe. org

Integrated Equipment – Scope Definitions • “Stick Built” • • Example: Programmed by the SI in the central Plant. PAx™ System “Integration” Skid has been delivered with a controller and programmed to run the skid processes SI to integrate into PAS for data collection and monitoring Clean Utilities WFI Storage & Distribution Ambient WFI Distribution Process Air Distribution N 2 Distribution Compressed Air Vapor Compression Still & Water Pre. Treatment Process Air (Compressor & Dryer) Multi-Effect WFI Still Scope Stick Built Integration Integration “Hybrid” Skid has been delivered with a functional controller and programmed Integration includes data collection and monitoring but also re -design of some aspects to integrate full with the Plant. PAx system Align graphics standards Coordinate operations with other equipment controlled by the Plant. PAx Connecting Pharmaceutical Knowledge ispe. org

Plant. PAx Components • Predefined library of AOI’s, global objects and faceplates • Examples: • VSD, HART Analog IO, Dual AI’s, Motors, Valves, Lead Lag Control • Modules come with detailed documentation • Faceplates support additional functions • • Plant. PAx Alarm Builder • • Interlocks, Permissives, Run-Time Monitor Auto-generate alarm list for control modules Software Decisions around Plant. PAX (Area Security coming in release 4. 5) Connecting Pharmaceutical Knowledge ispe. org

Factory. Talk Batch Implementation • Advantages • Built-in Phase. Manager in the Controller • Synchronization between PLC and FTBatch • Built-in faceplates and prompting • Pre-configured web-based batch reports • FTBatch View integrated into FTView SE Connecting Pharmaceutical Knowledge ispe. org

OEM Coordination • Project Design • Hardware Standard Coordination where possible (AB 1756 IO, SMC Manifolds, Arista HMI’s) • P&ID review and FS coordination • FAT Execution / Hardware • VM’s Loaded on small (7”x 8”) virtualization server for portability • Replicate production system at vendor site • Bring controllers to FAT for integration with vendor remote IO Connecting Pharmaceutical Knowledge ispe. org

Summary • Current status • Greenfield experience has been very exciting • Extended team has been very innovative and fun to work with • Fun is just getting started, target startup Q 4’ 19 • Thanks for coming! • Questions? Connecting Pharmaceutical Knowledge ispe. org