Giorgio Borghi  ‐MD MATRIC EuropaRome – March 24, 2011

MATRIC EuropaLife‐Changing Innovation

A New Resourcefor Process Optimization Studies

HIGHLIGHTS

ESTABLISHED: JANUARY 2010

MISSION:INDEPENDENT INNOVATION ORGANIZATION SERVICING INTERNATIONAL MANUFACTURERS 

– FOCUS ON CHEMICAL, ENERGY AND ENVIRONMENTAL TECHNOLOGIES• API AND SPECIALTY CHEMICALS MANUFACTURE• GREEN CHEMISTRY• ALTERNATIVE ENERGY AND ENERGY EFFICIENCY• POLLUTION CONTROL

– UNIQUE CAPABILITIES AND IMPACTS• PROCESS INNOVATION• PROCESS INTEGRATION• PROCESS INTENSIFICATION

BASING ITS COMMERCIAL VIABILITY ON CONTRACT WORK AND DEVELOPMENT OF  IP– BUILT ON SUCCESSFUL BUSINESS MODEL FROM UNITED STATES

LOCATION

Insubria BioParkat Gerenzano– Former multi‐national pharmaceutical research complex outside of Milan

– Available chemical and biological laboratories and pilot plants

– Utilizing technology developed at MATRIC, CPAC and other research centers

FIIRV – GERENZANO (VA)FORMER DOW‐LEPETIT SITE, VARIOUS OWNERS UNTIL DONATION BY PFIZER TO VARESE PROVINCE2006.GREAT EXPERIENCE IN ORGANISM GROWTH OPTIMIZATIONS AND COMPONENT ISOLATION ANDPURIFICATION TECHNOLOGY.

• EXTRACTS’ LIBRARY166.000 EXTRACTS CONSIDERED OF GREAT VALUE AND UNIQUE WORLDWIDE.

• STRAINS’ LIBRARYOVER 15.000 STRAINS ISOLATED FROM RARE ACTINOMYCETESCHEMICAL LIBRARYABOUT 10.000 MOLECULES, USEFUL FOR SEVERAL PRIMARY TESTS.

• ANTIBIOTIC LITERATURE DATABASECONCERNING NATURAL PRODUCTS OBTAINED BY FERMENTATION

THE R&D OF NEW ANTIBIOTICS WITH NATURAL ORIGIN FOR PREVENTION AND TREATMENT OFINFECTIVE DISEASES WAS THE PRIMARY ACTIVITY.IN THE FUTURE, FIIRV INTENDS TO BE AN ACTIVE PLAYER IN THE APPLIED BIOTECHNOLOGIES SECTOR.FOR THIS PURPOSE THE INCUBATED COMPANIES REPRESENT A STRENGTH OF THE INSUBRIASBIOPARK.

COMPANIES INCUBATED

• Actygea• Areta International• Chorisis• Creabilis Therapeutics• Cyathus Exquirere• D‐namic Consulting• Diasorin• Dr. Milanese• EMMtech

• HO.p.e.• ISB – Ion Source & Biotechnologies

• Istituto Ortopedico Galeazzi

• MATRIC Europa• Spepharm• Theo Servizi• Trueblue

“Challenges Related to Globalization for the Pharmaceutical Industry”  Jeffrey Gren, US dept. of Commerce, Feb. 22, 2010.

http://www.ita.doc.gov/td/health/2010austin_gren.pdf

API MARKET EVOLUTION

Cost analysis for the production of 2,4‐dihydroxybenzoic acid by aqueous Kolbe‐Schmitt synthesis

Fixed cost (capital 7 yr depr)       1 EuroRaw material                                38 EuroLabor                                             36 EuroWaste                                            14 EuroEnergy                                             1 Euro

Cost per kilogram of product at 4.4 t.p.a.

Chapter 13 “Micro Process Engineering”, volume 3 Wiley

KEY COST FACTORS

• Processing strategies that reduce labor costs will be required. 

• Specialty chemical and pharmaceutical producers are under intense pressure to reduce waste. Waste alone adds at least 400 Euros/kilo to the price of these products.

• Improve energy efficiency, lower operating and capital costs. Reduce solvent usage to be able to achieve more cost competitive performance.  

CONCENTRATION ON FLOW CHEMISTRY

MAIN ADVANTAGES OF FLOW CHEMISTRY:• YIELD & SELECTIVITY INCREASE.• MORE EFFECTIVE PROCESS CONTROL.• MORE UNIFORM PRODUCT QUALITY.• REDUCED NUMBER OF « TOUCHES ».• INCREASED SAFETY.• ELIMINATE INTERMEDIATE STORAGE (FOOTPRINT,  CAPITAL).• FACILITATE « REACH » COMPLIANCE.

WHICH RESULT IN IMPROVED QUALITY AND SUSTAINABILITY AND REDUCED COSTS.

RESEARCH PROJECT GOALS

Using multivariate real‐time measurement and data analysis techniques to rapidly generate high quality fundamental reaction information in lab scale equipment to enable holistic process intensification for bioprocesses and specialty chemicals production. Determining reaction information such as the reaction mechanism and rate expression information that is not convoluted with heat and mass transfer rates imposed by the lab equipment and can be used to scale‐up the process with the most cost effective processing approaches. 

TO REACH THE GOAL

• Develop fully automated and instrumented reaction characterization system based on micro‐scale flow technology; decouple reaction rate from heat and mass transfer properties of lab equipment.

• Demonstrate  use of the system to determine reaction rate expression; safely characterize reaction in novel operating windows.

• Develop similar capabilities for perfusion reactor for protein expression.  

PROJECT ACTIVITIES

Establish flexible and modular state‐of‐the‐art bio‐process and specialty chemical reaction characterization platforms with easily reconfigurable multivariate reaction characterization instrumentation to rapidly determine fundamental reaction parameters. Development of three related but different flow platforms:• a chemical reaction evaluation platform;• a catalyst, including immobilized enzymes, evaluation platform;• an organism growth platform based on perfusion reactors.

All platforms to benefit from the design and installation of a multifunctional NeSSITM substrate with appropriate flow control and conditioning components arrayed about the microreactor and analytical probes mounted for rapid microreactor characterization. 

A3

A2A1

A5A4

Standard Reactor Blocks A + B :

• 1 SJI • 2 SJH• 6 RTH

Reactor Block A

Reactor Block B

CURRENT GERENZANO LABORATORY REACTOR SET‐UP

Corning LFR

LFR = Low Flow Reactor

MODULE LIBRARY

Stacking scale-outGen I

Gen III scale-out

Gen II scale-out

Gen I, II, III Production banks

EXAMPLE OF REACTION IN NOVEL OPERATING WINDOW

EXAMPLE OF REACTION IN NOVEL OPERATING WINDOW

• Optimization of acid catalyzed transesterification of seedoils with methanol for the production of biodiesel.

• Reaction studied extensively at MATRIC, extensive dataexist for production in batch and continuous systems.The mixing of the high molecular weight triglycerides inlarge batch reactors has a significant impact on rates andyields as does the phase separation of the productglycerol which removes the catalyst from the reaction.

• Useful chemistry to evaluate the use of enzymes tocatalyze the reactions since base catalysis is not asefficient with the high free fatty acid levels found in non‐food oils. Study of this important reaction will enable tocompare the two catalyst approaches and provide auseful test of the platform capabilities.

CHEMISTRIES

CHEMISTRIES

• Optimization of continuous production of pre‐polimers from MDI and TDI with PEG 600 and otherdiols in THF above boiling point (80°C).

• Continuous Production of Calcium and Sodium Formateand Propionate (Food Additives)

PERFUSION CELL FOR TISSUE GROWTHFEED-UNIT OPERATION-PAT

PROTEIN THERAPEUTICS ARE A MAJOR PART OF API PIPELINE

PERFUSION CELL FOR TISSUE GROWTH

PERFUSION CELL FOR TISSUE GROWTHAND/OR CONTINUOUS PROTEIN PRODUCTION

The Seattle Sensor Systems SPR analyzer uses “Plasmon Resonance" (SPR) chips, named Spreeta2000 to detect and/or quantify biological materials in an aqueous suspension or solution.

New generation of biobased sensors in a 24 independent measurement channel format. This device only uses 350nl for a sample.

SPR LAB ON A CHIP

NUTRIENT CHARACTERIZATION

Key Issues:• Very complex mixture• Composition of nutrient mixture may drift• Relationship of nutrient composition to protein production 

not fully understood• No one characterization method can detect all the nutrient 

composition variability• Data from characterization methods will drift

Complex Feeds

Refineries also face the problem of complex feeds and must understand their properties to optimize operations 

ANALYSIS OF COMPLEX MIXTURES

• Raman spectroscopy can characterize key components in very complex mixtures• Data collection is usually about a minute• Data analysis tools that were used with the NMR and GC data can be used to 

present the information in a class format for easier understanding of changes 

The complex nutrient media can be more precisely characterized by using additional analysis tools such as elemental analysis for metal ions.  This data is then fused for a much more powerful characterization tool

DATA FUSION

• There are a significant number of batch producers that need to change the way they do business or face serious problems.

• Conversion to continuous processing supported by PAT could help be a useful approach to their cost problems.

• The use of microreactors is important as an indication of state-of-the-art technology

• Availability of different platforms and tools is an important factor in convincing manufacturers to resort to CRO’s

CONCLUSION

REACTORS AND PAT ARE ONLY PART OF THE STORY:

PROCESS INTENSIFICATION REQUIRES THE INTEGRATION OF REACTORS, SEPARATION TECHNOLOGY AND ANALYTICAL TECHNOLOGY.

Thank you

MATRIC Europac/o Biopark Insubrias – via Roberto Lepetit 34 21040 Gerenzano (VA), Italycontact: matric@matriceuropa.comwww.matricresearch.com/MATRIC-Europa.asp