2. 2
Agenda
Grifols Overview
Grifols Engineering
Innovations in
- Plasma Collection
- Testing
- Pooling
- Fractionation
- Purification
- Filling
“Developing new technologies to
provide innovative solutions is
a core value to Grifols”
3. 3
Grifols Overview
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.
Hospital Division – Manufactures standard parental solutions, medical devices and logistics platforms for
hospitals
Diagnostics Division - Supplies industry with clinical analysis and laboratory testing tools. Produces
analyzers, reagents, instrumentation and products to collect, process and store blood
Bioscience Division - Treatment of medical conditions using blood components. Plasma collection and
testing, manufacturing, marketing and sales, R&D
Bioscience manufacturing sites 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
Madrid Stock Exchange: GRF.MC
Nasdaq: GRFS
Stock Information
4. 4
Grifols Engineering
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Plasma Fractionation Technology
Developing new technologies and expertise to provide innovative solutions is a core value tor
Grifols since founding of the company.
Inheriting this spirit Grifols Engineering was established in 2001 to provide engineering solutions within the
company but also to other pharmaceutical clients.
External Experience
Engineering projects include consulting, process engineering,
feasibility studies, conceptual and detail design, construction and
start-up services
Machinery projects include specialized equipment for the
fractionation industry, purification and fill lines.
5. 5
Innovations in Plasma Collection
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In 1951 José Antonio Grifols Lucas invents Plasmapheresis
which combined with the work of Edwin Cohn paved the way
for the Plasma Fractionation Industry.
Plasmapheresis removes cells and platelets from whole blood via
centrifugation. The cell fraction is returned into the donor allowing
weekly donations. Approximately 800 ml of plasma is collected per
donation.
Grifols owns more than 150 donor centers in the US collecting 7.5
million Liters in 2014.
Grifols Academy of Plasmapheresis provides one of a kind
training and continuous improvement for the industry.
PediGri® On Line allows healthcare professionals to access lot
specific quality and safety information down to the individual donors.
6. 6
Plasma Bottle Sampling
Guarantees plasma sample is traceable to correct bottle by only allowing sampling if test tube
barcode matches bottle.
Machine designed and built by Grifols Engineering.
PBS
Fully automated label
printing, labelling,
barcode matching and
sampling.
PBS Lite
Barcode matching and
sampling
7. 7
Innovations in Testing
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Grifols Diagnostics is leading manufacturer of instruments, reagents and test kits:
• NAT – Testing
• ELISA
• Gel Cards
2014 Grifols purchases Novartis blood transfusion diagnostics business
8. 8
North Fractionation Facility (NFF)
Key Figures
Location: Clayton, NC
Size: 150,000 sq. ft.
Project Cost: $ 342.6 million
Construction Duration: 24 month
FDA Licensure: November 2014
without pre-approval inspection!
Project Goals & Achievements
Provide high-throughput manufacturing facility with minimal risk to 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
9. 9
Pooling
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Combination of up to 11,000 frozen individual donations into single batch
Challenges of Pooling
• Thawing and combination process needs to be fast to minimize loses in product
yield
• Difficulties in opening and emptying individual donations containers (bottles or bags)
to remove frozen product
• Open product needs to be handled in Class C
• Large amount of material handling (donations in, frozen product out, pallets and
totes out, wastes out)
Traditional Approach
• Labor intensive manual process with bio-burden and injury risks.
• Thawing and recovery rate of each individual donation is highly inconsistent
1 L Plasma Bottle
0.5 L Plasma Bag
10. 10
Loading Side
1. Manual Loading of Bottles
2. Skin-Thaw with Hot water
3. Rinse with AWFI
Unloading Side
4. Air blow to dry bottles
5. Cutting station to open bottle
• Bottle lids are discarded into waste chute
6. Robot empties frozen plasma slugs into chute to
vessel
• Detects failure to eject via weight change
7. Drip from empty bottles is collected for extra
recovery
8. Empty bottles discarded into waste chute
Automatic Bottle Opener
Loading side in Class D
Unloading side in Class C (Level below contains Pooling vessels)
Designed and built by Grifols Engineering
11. 11
Method to skin-thaw is similar as for bottles
• Two parallel conveyers in single tunnel to increase
throughput.
• Extended drying due to irregular bag shape
Novel Plasma Bag Opener
1. Robot grabs bag and pulls it across stationary
knife
2. Two rollers squeeze frozen plasma block out of
plastic.
3. Camera system automatically detects
unsuccessful discharge.
• Two parallel robots work independently to increase
pooling rate
Plasma Bag Opener
Designed and built by Grifols Engineering
12. 12
Minimization of residence time to increase cryoprecipitate yield
• Optimization of heat-transfer by utilizing horizontal thaw vessels
• Two parallel pooling trains to shorten duration
• Semi-continuous by starting product separation while
Vertical Facility Integration
• Pallet lifts to transport plasma from ground floor and return empty pallets and totes
• Empty bottles and caps fall to ground floor
• Frozen plasma fall via chute to horizontal thaw vessels on mezzanine below
Semi-Continuous Pooling Train
Plasma
Plasma Lift
Waste
Automatic Bottle Opener
Horizontal Thaw
Vessel
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Fractionation
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Successive additions of ethanol and buffers and temperature changes precipitates certain protein
“fractions” from the plasma. Proteins are then separated from the liquid via filtration or
centrifugation
Challenges in Fractionation
• Sub-freezing process requires 23ºF (-5ºC) work environment
• Separation equipment typically involves open processing with manual removal of solids from filter-
presses or centrifuges
• Separation equipment often requires manual cleaning
• Open handling of ethanol requires expensive electrical installations
• Open processing requires extensive clean-room areas
14. 14
Innovations in Precipitation
NFF Equipment Features
Development History for NFF Process
• 1995: Precipitation optimization studies
• Long-term data collection and statistical
evaluation to optimize process
• 2008: Confirmation at 1,000 L
manufacturing scale
• 2014: FDA licensed in 13,000 L scale
• Vessel closed during processing and placed completely in ambient technical space, not in cold clean room
• Closed buffer and ethanol addition from central distribution systems
• Scale-up to 13,000 L.
• No manual preparation for CIP.
NFF Process Features
• Optimized precipitation enabled world’s largest fractionation batch size of 9,000 L plasma
• Increased buffer and ethanol addition rates to shorten cycle-times.
15. 15
Innovations in Separation
Development History with GEA Westfalia
• 1998: Collaboration with 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
• 2014: FDA licensure of NFF building containing
fourteen BSH-30 machines
Machine Features
• Disk-stack centrifuge including CIP and SIP
• Closed processing except for solids removal
• Only bowl and solids collection is in clean room
• Support skids are located in technical space
outside of clean room
• Optimized solids and liquid recovery
• Direct bowl cooling via liquid nitrogen to ensure
sub-freezing separation temperature
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Purification
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Purification processes in Plasma Fractionation start
with intermediate “pastes” and use typical purification
unit operations used throughout biotech:
• Ultrafiltration
• Chromatography
• CIP
The fractionation industry has special requirements
related to viral inactivation / removal steps which
include:
• Solvent Detergent treatment
• Thermal inactivation
• Nanofiltration
120 m2 Ultrafiltration Skid designed by Grifols Engineering
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Skid Design and Manufacturing
Grifols as manufacturer of pharmaceuticals also designs and
builds purifications skids in-house by Grifols Engineering
Main advantages:
• Better cost, schedule and scope control
• Design experience remains within company
• Automation can be developed specific to manufacturing
needs and software design experience greatly supports
future troubleshooting
• Turn-over packages assembled for specific business
needs to support for IOQ
Nanofiltration system Ultrafiltration Skid
Ultrafiltration Skid
18. 18
Innovations in Filling
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Protective cap over stopper and vial guarantees sterility by providing
labyrinth seal for microbes (principle of Pasteur flask).
Cap is removed only seconds before actual fill and stoppering
providing maximum protection.
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Innovations in Filling
Typical Filling Line
Grifols Sterile Filling Line
Single continuous line
Decoupling of equipment
Autoclave instead of depyrogenation oven provides decoupling of single equipment train to
• lessen impact of equipment failure
• allow staging of sterile vials before filling operation for fast product change-over
Autoclaving fully assembled vials also provides easy sterilization of stopper
Protective cap
maximizes protection
Sterile staging for fast
change-over
No separate stopper
sterilization required
