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Grifols’ North Fractionation FacilityFOYA Winner – Project Execution

Dieter Fassnacht

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AgendaIntroduction to GrifolsNorth Fractionation Facility Project- Key Goals and AccomplishmentsHighlights 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 PlasmaOther Highlights- Reduced Risk to Product Quality- Manufacturing Efficiencies- Facility Integration

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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 Acquisitions2011: Grifols acquires Talecris Biotherapeutics for $ 3.4 billion2014: Grifols acquires Novartis Diagnostics Unit for $ 1.7 billion

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North Fractionation Facility (NFF)

Key FiguresLocation: Clayton, NC, US

Size: 150,000 sq. ft.

Project Cost: $ 342.6 million

Construction Duration: 24 month

Status: Awaiting FDA PAI

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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 JustificationIncrease companies fractionation capacity to fulfill patient demands

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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

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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

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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

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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

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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

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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

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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 .

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Leveraging Construction & Commissioning for IOQ

Commissioning Approach

MIV (Main Instrumentation Vendor) ApproachSelection 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

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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.

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Other Highlights: Reduced Risk to Product Quality

• Validated a closed process to eliminate contamination risk and 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

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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

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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

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Thank you ISPE for Recognizing our Effort and Accomplishments!