novel fractionation technologies interphex

Novel Technologies for Human Blood Plasma Fractionation

Dieter FassnachtGrifols

Booth 1736

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AgendaGrifols OverviewGrifols EngineeringInnovations in

- Plasma Collection- Testing- Pooling- Fractionation- Purification- Filling

“Developing new technologies to provide innovative solutions is a core value to Grifols”

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Grifols OverviewGrifols 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 hospitalsDiagnostics Division - Supplies industry with clinical analysis and laboratory testing tools. Produces analyzers, reagents, instrumentation and products to collect, process and store bloodBioscience Division - Treatment of medical conditions using blood components. Plasma collection and testing, manufacturing, marketing and sales, R&DBioscience manufacturing sites 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

Madrid Stock Exchange: GRF.MCNasdaq: GRFS

Stock Information

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Grifols Engineering

2 TESTING POOLING3 FRACTIONATION4 PURIFICATION5 FILLING61 COLLECTION

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 ExperienceEngineering projects include consulting, process engineering, feasibility studies, conceptual and detail design, construction and start-up servicesMachinery projects include specialized equipment for the fractionation industry, purification and fill lines.

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Innovations in Plasma Collection


In 1951 José Antonio Grifols Lucas invents Plasmapheresiswhich 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.

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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.

PBSFully automated label printing, labelling, barcode matching and sampling.

PBS LiteBarcode matching and

sampling

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Innovations in Testing


Grifols Diagnostics is leading manufacturer of instruments, reagents and test kits:• NAT – Testing• ELISA• Gel Cards2014 Grifols purchases Novartis blood transfusion diagnostics business

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North Fractionation Facility (NFF)Key FiguresLocation: 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 & AchievementsProvide 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 automationMaximize yields while maintaining product quality• Optimized processing methods and decreased physical lossesLower long-term operational costs• Minimized clean room production space with no cold processing rooms.• Reduced labor costs due to scale, automation and improved technology

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Pooling


Combination of up to 11,000 frozen individual donations into single batchChallenges 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

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Loading Side1. Manual Loading of Bottles2. Skin-Thaw with Hot water3. Rinse with AWFI

Unloading Side4. Air blow to dry bottles5. Cutting station to open bottle

• Bottle lids are discarded into waste chute6. 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

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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

knife2. 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 OpenerDesigned and built by Grifols Engineering

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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


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

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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.

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Innovations in SeparationDevelopment 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


Purification processes in Plasma Fractionation start with intermediate “pastes” and use typical purification unit operations used throughout biotech:• Ultrafiltration• Chromatography• CIPThe 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 EngineeringMain 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

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Innovations in Filling


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-overAutoclaving fully assembled vials also provides easy sterilization of stopper

Protective cap maximizes protection

Sterile staging for fast change-over

No separate stopper sterilization required

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Thank you!Please visit us at booth 1736

novel fractionation technologies interphex

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