2. 2
Agenda
Introduction to Grifols
North Fractionation Facility Project
- Key Goals and Accomplishments
Highlights in Project Execution
- Drive Development of Key Technologies
- Perform Detailed Feasibility Studies
- Design Competition to Find A&E Partner
- Establish & Maintain Strong Project Team
- Control Project with Devoted Steering Committee
- Modular Construction
- Functional Testing During Construction
- Leveraging Construction & Commissioning for IOQ
- Engineering Test Runs with Plasma
Other Highlights
- Reduced Risk to Product Quality
- Manufacturing Efficiencies
- Facility Integration
3. 3
Grifols Overview
2 TESTING POOLING3 FRACTIONATION4 PURIFICATION5 FILLING61 COLLECTION
Plasma Fractionation Technology
Grifols is the world’s third largest producer of plasma derived medicines.
We are dedicated to developing innovative healthcare products and services while maintaining the
highest ethical standards for patients and employees across the globe.
The company has 12,000 employees worldwide committed to serving patients affected by life-threatening
conditions.
Manufacturing sites producing plasma-derived pharmaceuticals are located in Parets del Vallès, Spain
(close to Barcelona), Clayton, NC and Los Angeles.
Recent Acquisitions
2011: Grifols acquires Talecris Biotherapeutics for $ 3.4 billion
2014: Grifols acquires Novartis Diagnostics Unit for $ 1.7 billion
4. 4
North Fractionation Facility (NFF)
Key Figures
Location: Clayton, NC, US
Size: 150,000 sq. ft.
Project Cost: $ 342.6 million
Construction Duration: 24 month
Status: Awaiting FDA PAI
5. 5
Provide high-throughput manufacturing facility with minimal risk to product quality
- World’s largest batch size of 9,000 L and annual capacity of up to 6 MML
- Maximized closed processing and incorporated high level of automation
Maximize yields while maintaining product quality
- Optimized processing methods and decreased physical losses
Lower long-term operational costs
- Minimized clean room production space with no cold processing rooms.
- Reduced labor costs due to scale, automation and improved technology
Deliver the facility in an aggressive timeframe and under budget
North Fractionation Facility (NFF)
Project Goals & Achievements
Project Justification
Increase companies fractionation capacity to fulfill patient demands
6. 6
Drive Development of Key Technologies
Centrifugation (GEA Westfalia)
Precipitation
• 1995: Precipitation optimization studies
• Long-term data collection and statistical evaluation to
optimize process
• 2008: Confirmation at 1,000 L manufacturing scale
Bottle & Bag thawing and opening
• 1998: Collaboration between Bayer and Westfalia to
develop unique centrifuge for fractionation
• 2000: First BSH-30 centrifuge tested
• 2004: Second generation machine tested
• 2007: Third generation machine tested
• 2013: FDA licensure of BSH-30 centrifuge
• In-house equipment innovation by Grifols Engineering
7. 7
Perform Detailed Feasibility Studies
New Fractionation Facility
Site (Evaluation of Utilities, Infrastructure and Building Location)
• 2003: Infrastructure Feasibility Report
• 2008: NFF Site Feasibility Study
• 2006: Fractionation Strategy
• 2008: Report on New Fractionation
Stakeholder Approval
- Manufacturing
- Engineering
- Technology
- Quality
- Regulatory Affairs
Ready to Launch
Capital Project
Table of Content
- Executive Summary
- Process Design
- Manufacturing Plant Concepts
- Building Description
- Utilities and Infrastructure Requirements
- Development Strategy and Technology Base
- Regulatory Outlook
- Project Timeline
- Project Cost Estimate
- Open Issues and Risks
8. 8
Design Competition to Find A&E Partner
Bid Process for Conceptual Engineering
included Design Competition to
Pre-Screening
• Three A&E firms were identified to be suitable partners
based on comprehensive survey of existing large scale
bioscience facilities and EPCV experience
• challenge Feasibility Study
• develop new concepts and ideas
• assess teams, collaboration and creativity
Valuable Results included:
- Building location, orientation and size
- Vertical integration / logistics
- Creative concepts around unique
process steps
Team selected Fluor as Partner for the Project
9. 9
Establish and Maintain Strong Project Team
Collaboration with A&E firm to form
“one” team
Staffing
• Grifols Team maintained continuity from Conceptual
Engineering through Validation.
• Project Team also included from “day one” dedicated
resources from
• Plant Engineering incl. Maintenance
Supervisor and Technicians*
• Production Manager and Supervisor
• Technology (R&D)
• Quality
• Validation
Senior Management committed in Project
Charter to
“support the right resources at right time”“maintain critical team members and sufficient
overall staffing”
• Grifols and Fluor formed fully integrated
team.
• Team worked out of Greenville, SC.
• Grifols key team visited Greenville every
two weeks.
* As presented at 20th ISPE CASA Life Sciences Technology Show
by Brent Noel and Detlef Kehm
10. 10
Control Project with Devoted Steering Committee
Steering Committee
- CEO
- CFO
- SVP Manufacturing (Site Head)
- SVP R&D
- SVP Corporate Compliance
Principals Meeting
- SVP Manufacturing (Site Head) - Program Director
- VP Engineering - Project Director
- VP Manufacturing - Finance Director
- VP R&D - Supply Chain Director
- VP Quality - Fluor Senior Management
- VP Regulatory Affairs - MIV Management
- VP Finance
NFF Team Leaders
Meets Monthly
11. 11
Modular Construction*
* As presented at INTERPHEX™ 2013 by Detlef Kehm, “Large Scale
Process Modules First in Place Technology”
Benefits for On Site Super Skid Fabrication
• Controlled conditions in fabrication shop leads to higher quality and
safer environment
• Reduced congestion and coordination in the building
• Increased productivity due to high quality of specialty workforce
• Simultaneous construction of Building including Infrastructure and
Process Modules enabling schedule compression by 4 months.
• Large “off shore” pool of resources can be utilized concurrently
• Standardization leads to assembly line approach
12. 12
Functionality Testing during Construction
Construction approach
• One of seven Centrifuge Piping skids was accelerated
to provide early functionality testing. This skid would
also be the last one to be installed in NFF
building to maximize testing duration
• Test Stand installed to provide structure for centrifuge
and all utilities to enable testing.
Benefits
• Significant software modifications occurred during four
months testing period while facility was still in
construction leveling future resource demands.
• Only minor piping modifications confirmed thorough
skid design.
Objective
• Obtain head-start for functional testing and debugging
of most complicated process equipment of project
• Also allowing possible last minute piping changes
to other skids .
13. 13
Leveraging Construction & Commissioning for IOQ
Commissioning Approach
MIV (Main Instrumentation Vendor) Approach
Selection of MIV partner for entire project allowed single point of contact to perform RV (receipt
verification) of instruments which included 3rd party quality inspection prior to shipment to site or
fabricators
• Utilize validated database and formal protocols (FAT, commissioning) to allow leveraging for IOQ.
• Commission equipment according to same system boundaries as IOQ
• Use formal Project Change Control to bridge changes between verification and qualification
Asset Database
• Validated database was used to populate asset attributes during construction including receipt
and installation verification
• Bulk upload into site maintenance system (Maximo) upon completion of individual systems
Commissioning
IV protocols
OV protocols
Qualification
IQ protocols
OQ protocols
upload data, calibration done, project changes closed
draft procedures, testing with product, changes closed
14. 14
Engineering Test Runs with Plasma
Benefits of Testing with Plasma
• Final tweaking of parameters specifically to optimize
separation temperatures could only be executed with
plasma.
• Many OQ test cases used product instead of a water /
ethanol surrogate increasing confidence in successful
process validation
Plasma Industry’s Challenge for Product Testing
• Released plasma cannot be used for test runs due to high
costs of almost $1 MM per batch and resulting lack of final
product in the market
• Pathogen Safety prohibits use of untested, released plasma
Securing Plasma for Test Runs
• Over 60,000 Liters of tested plasma (not for production
use) was secured over five years to enable testing of
NFF process.
15. 15
Other Highlights: Reduced Risk to Product Quality
• Validated a closed process to eliminate
contamination riskand reduce the
cleanroom space
• Collaborated with Grifols Engineering to
develop a robotic bottle opening system to
eliminate potential plasma contact with
operators (Installation of plasma bag
opening system is in progress)
• Employed automation systems reducing
human error and increase process
reliability
16. 16
Other Highlights: Manufacturing Efficiencies
• Effected a 100% increase in site output to
6 MML plasma per year
• Automation and equipment functionality
lowered labor per liter fractionated by 40%
• Increased process yield between 8 and
15% by leveraging Grifols advanced
understanding of processing human
plasma
• Achieved a 31% reduction in energy per
liter with closed process in ambient space
• Reduced chemical costs by $1 million
annually by employing bulk chemical
storage and distribution
17. 17
Other Highlights: Facility Integration
• Produced modern sustainable facility that
eliminates harsh cold work environments,
while achieving excellent functional
arrangements resulting in a minimization of
material movement
• Contained manufacturing operations on a
single level.
• Minimized cleanroom footprint to 12% of
gross space
• Directing vertical transfer between levels
produced simplified horizontal flow paths
• Applied broad use of windows and natural
light
