Robert Valdes

Large-Scale Manufacturing Story:Keeping Pace with Chinaʼs future Biosimilar Demand

Introduction

• Biosimilar Drivers & Challenges in China

• Large-Scale Manufacturing Story

• Business Justification - Commercialization (>10 years)

• Key Success Factors

IntroductionRobert Valdes (Bob)GMP Consultant and V.P. Business DevelopmentBiotech Resources, USA

22 years experience in biotechnology: ManufacturingHuman Genome Sciences, Lonza, Charm Sciences

Advisory Board—Johns Hopkins (2011)Co-Founder—Biotech Resources (2000)Founder—RRMS Inc. Supporting the MS Community (2002)

BA Microbiology—University of New HampshireMSc Biology / BioProcessing—University of MassachusettsMBA—Johns Hopkins Carey School of Business

Biosimilar Drivers & ChallengesDrivers

New Sector / High Economic Potential

• 12th 5-Year Plan: Healthcare Reform

• Expected Discount vs. Innovator• Rising Prosperity / Treatment naïve

• Customer price sensitivity: High• Large Market / High CAGR %

• Success, Time, Cost: Favorable

Patent Expiry: $54Bb before 2020

Blockbusters Lose Patent Protection before 2020: US$54Bb

http://www.gabionline.net/Biosimilars/Research/US-54-billion-worth-o f-biosimilar-patents-expiring-before-2020

Biosimilar Drivers & ChallengesChallenges

• Marketing & Differentiation • Product Approval does not guarantee revenue

• Innovator has 20 yrs collective experience

• Switching Costs: Physicians need data • May impede adoption / market penetration / delayed revenue

• Innovatorʼs 2nd/3rd generation Biobetter

Biosimilar Drivers & ChallengesChallenges

• Competition: Innovator vs BioSimilar

• Kilograms / Annum: High

• Facility Expansion, Build New or Partnership

• Cost ($/gram) control to hedge against expected discount and NDRC/NRDL action

• Project: Strict Adherence to Quality/GMP

• Manufacturing Process is complex

Large-Scale Manufacturing Story• Project map: 50,000 ft view

• Business Rationale & Justification• Core Team Hiring and Training

• Quality Systems• Design Development—Procurement—Start-up -Comm/Val

• Equipment / New Technologies• Strategic Alliances & Benchmarking

• BLA Approval & Celebration!

Large-Scale Manufacturing StoryProject map: 50,000 ft view

0

25

50

75

100

Business Rationale Design & Project Planning Execute Release for GMP

Project Expenditures

Large-Scale Manufacturing StoryBusiness Rationale & Justification

• Facility: Capital appropriation >$100MM ($1000/ft2 US)

• Working Capital = Raws + WIP +BDS+FDP

• Financial Evaluation: pipeline, customer need (kg), pricing, royalty burden, 2-4 years, innovator / FOB / BioBetter

• Scenarios: CMO vs Build vs JV

• Scenarios: Scale vs Titer vs $/gram

• Key Success Factor #1: Alignment on cost, time, resources, and risks. All departments highly participative

Large-Scale Manufacturing StoryCore Team Hiring, Ramp-up, and Training

• Key Success Factor #2 : Hire the core team early

• You will always be training / Develop training system with QA (Quality Assurance) as workers commission the facility.

• Hiring takes time. Training takes time. Priority.

0

50

100

Core Team Design / Plan Execute GMP (1/2 Max) Full Speed

Percentage of Fully Staffed Facility

Large-Scale Manufacturing StoryQuality Systems

QSIT (21 CFR Part 820)Quality Systems Inspection Technique: Evaluate effective implementation of Quality Systems / Subsystems and satellite programs

• Goal: Determine the firmʼs state of compliance by focusing on the key elements from a top-down perspective.

• Quality Policy, Quality Plan: translated into procedures/activities/Instructions relevant to the product produced

• Management Reviews (suitability and effectiveness of the Quality System)

• Evaluate subsystems for adequacy based on findings, trends; Metrics

• Leverage electronic systems early: CAPA, Training, Documents, Metrology, Inventory

• Leverage electronic systems early: Data Monitoring, EBR, Barcode, Wireless Scan

http://www.fda.gov/downloads/ICECI/Inspections/UCM142981.pdf

Large-Scale Manufacturing StoryQuality Systems (conʼt)

QSIT (21 CFR Part 820)Key Success Factor # 3-QA/QC will integrate very early to provide guidance on design as it pertains to:

• Material Systems

• Facility/Equipment System Management

• Production Systems—Batch Records, Tech Transfer

• Microbiology—Environmental Control, Facility/Personnel Hygiene

• Training (always training)

• Personnel Flow, Waste Flow, Segregation, Facility Protection

• Product Sampling / Testing: Analytical Chemistry, Immunoassay, PCR

Large-Scale Manufacturing StoryDesign Development

• Conceptual/Prelim Design: Process Description, PFD, Facility Energy/ Utility balances, Major Equipment Lists, General Arrangement , Site Plan, Design Bases (Piping, Electrical, Equipment, Civil, Structural), Cost estimate summary

• Detailed Design: Utility Summary, Equipment Specs, Diagrams, 3D-model

• Procurement & Construction Management, Safety, Quality, and Permitting

• Definitive Cost estimate

• Start-Up/Commissioning / Validation

• Engineering Runs and Release for GMP

Large-Scale Manufacturing StoryEquipment and New Technologies

• Manufacturing Strategy must be designed for ease of scale-up and tech transfer

• Insource and Outsource as part of facility utilization model

• Innovator and Biosimilar companies have access to modern technologies

• Expression systems, Upstream, Bioseparation, etc

• Deploying new technology platforms should have thorough regulatory review

• Long lead times and price: bioreactors, columns, Centrifuge, BDS freeze units

• Lead times will force the order of procurement and resource deployment

Large-Scale Manufacturing StoryStrategic Alliances & Benchmarking

• Key Success Factor #4: Leverage peerʼs experience to compress learning curve• Facility Design: Design ideas / Lessons learned / PAI trends• Optimize facility utilization and supply continuity• Internships / Training

Large-Scale Manufacturing StoryBLA Approval and Celebration

• >10 years

• Design, Build, Operate 24/7 to provide phase III and commercial supply

• Key Success Factor #5: Celebrate along the way

Database Lock BLA Filing PAILAUNCH!

ASSEMBLE APPROVAL

Large-Scale Manufacturing StoryKey Success Factors

Key Success Factor #1: Must alignment on cost, time, resources, and risks. All departments project aware

Key Success Factor #2: Hire the CORE team early

Key Success Factor #3: Integrate with QA/QC early in project

Key Success Factor #4: Benchmark / Learn from peers

Key Success Factor #5: Celebrate along the way

Thank YouRobert Valdes (Bob)GMP Consultant and V.P. Business DevelopmentBiotech Resources, USAbobv@bobv.net