Generating Customer Value with

Renewable Chemicals:

The Case for Fermentation

CollaborationChristopher J. Guske, Ph.D.

D2 Biotech Consulting, LLC

BIOWC17

The Next New Adventure…

Christopher J. Guske, Ph.D.D2 Biotech Consulting, LLC

Former Director, BioVentures and

Support Services, Tate & Lyle

Nearly 30 yrs of Biotech experience

(CP Kelco, NutraSweet, Tate &

Lyle)

Fermentation subject-matter

expert

Downstream conversant

Process R&D expertise

Dennis AdkessonIndependent Consultant Associate

Research Fellow, Tate & Lyle, and

VP, Engineering, DTL

Over 50 yrs corn wet mill

experience (Tate & Lyle)

Over 20 yrs of Biotech experience

Downstream subject-matter expert

Fermentation conversant

Engineering expertise

Key Industry Milestones Interfaced with/assessed ~100 biotech opportunities/companies.

1,3-propanediol (PDO; DuPont Tate & Lyle BioProducts): Process development (multiple strain generations, scale-down experiments, media optimization, etc.), pilot plant scale up (fermentation and downstream), plant design, and Loudon, TN, plant startup support. Fermentation scaled from 13kL to 600kL, hitting 95% of pilot performance at startup and exceeding thereafter. Achievement widely recognized as the Gold Standard in Industrial Biotechnology; received the 2007 American Chemical Association’s Heroes of Chemistry Award.

1,4-butanediol (BDO; Genomatica): Produced 5Mlb of BDO at 600kL scale (DTL BioProductsPDO facility) after 14 months of lab and pilot plant work, including several strain generations and upstream and downstream process optimization; process was recipient of 42nd Kirkpatrick Chemical Engineering Achievement Award.

Farnesene (Amyris): Contract manufacturing in Decatur, IL; process optimization reduced production costs 2-3x; process received a 2014 Presidential Green Chemistry Challenge Award.

Polyhydroxyalkanoate (PHA; DaniMer Scientific): Technical demonstration and scale up of strains.

Astaxanthin (Igene JV): Small-scale lab and on-site plant support resulted in a 650% titer and productivity increase, resolving issues of scale-up in a converted citric acid plant.

D2 Biotech Consulting, LLC/Adkesson Experience

Process conceptualization and economic evaluation for both operating and capital costs.

Small-scale development (10L) through large scale (600 m3) production fermentation experience, including mechanically agitated and bubble column bioreactors and diverse operating rheologies (low to high viscosity, Newtonian and Non-Newtonian).

Process development, technical transfer, troubleshooting, process analysis, experimental design and applied statistics, tracking and optimization, cost reduction, downstream recovery, bioreactor design, plant startups, strain evaluation, media development and optimization, and scale up/scale down experience.

Experience with diverse products, processes, and organisms.

Broad knowledge of downstream unit operations.

New product development at pilot scale.

Project management for both R&D and plant capital projects (≤$100MM)

Broad knowledge of corn wet milling industry

Green Chemistries Dominated by Fermentation

Microbes are amazing entities:

Small, self-replicating, self-healing, chemical factories

Simultaneous, complex chemistries under mild operating conditions

Can be easily retooled

Diversity of products from the same hardware footprint

Low carbon footprint relative to petrochemical routes

Potential exceptions:

Inorganic catalysis to perform backbone modifications (e.g., Rennovia)

Reactions requiring extreme temperatures or pressures, or toxic chemicals

Post-fermentation chemical modifications

Enzymatic conversions

Fermentation Processes are Highly Diverse Diversity of organisms:

Diversity of operating conditions:

Key points:

Fermentation is part art and part science

A lot of things need to go right to have a good outcome. All it takes is for one thing to go wrong and all the things done right get flushed down the drain.

E. coli S. cerevisae Phaffia Aspergillus

PPFMs Pichia Yarrowia Cyanobacteria

Actinomycetes Algae Methanotrophs CB1

pH Temperature Dissolved oxygen Media comp.

Batch Fed-batch Continuous Asepsis

Agitation Aeration Sterilization Contamination

Fermentation Processes are Highly Diverse

Diversity of recovery/purification processes:

What is the strategy?

What technologies are required?

Filtration IX Carbon Centrifugation

Evaporation Crystallization Distillation Chromatography

Solvent extraction Electrodialysis

Intracellular Extracellular Gas Liquid

Solid Background

matrix

Coproducts/

contaminants

Purity

Fermentation Processes are Highly Diverse

Diversity of Feedstocks:

Feedstock factors to consider:

Geography: sourcing, transportation, co-location, etc.

Price volatility

Purity:

Impact on downstream?

Cheap/unrefined: Are you taking out someone else’s trash?

Cost-yield relationship

Glucose Fructose Sucrose C5/C6

Starch Glycerol Vegetable oils Molasses

CSL Organic acids Alcohols Industrial gases

Product vs. Process Customer needs drive green chemistry products:

“Greener”

“Smaller carbon footprint”

“Take the (inefficient) animal out of the process”

“Better for the environment/environmentally friendly/better

specificity”

“Petrochemical replacement”

Green products are identified…then the question is how to

produce them in an economically and commercially viable

way?

“If scale up was easy, everyone would be doing it.”

Fermentation Process Development

It is very rare that any one company can do it all:

Nothing is “textbook.”

Nothing is as easy as you think it is.

You don’t know what you don’t know.

There will be “snakes in the grass.”

The key: Know your strengths and weaknesses and

collaborate with those who know

Who has the missing expertise?

Where can speed to market be gained?

Who has the hardware/capital to implement?

Who has an established track record of success?

Successful Collaborations Genencor, DuPont and Tate & Lyle: 1,3-propanediol

Genencor/DuPont strain collaboration

Fermentation “beauty contest”

100 Years of Corn Wet Milling: experience processing and separating biological

materials at large, economic scale

Plant construction experience

Feedstock backwards integration and co-location

Successful Collaborations Genencor, DuPont and Tate & Lyle: 1,3-propanediol (cont.)

A fully integrated development process

Successful piloting

Successful commercial launch

Successful Collaborations Genomatica and Tate & Lyle: 1,4-butanediol

14 month piloting: process very similar to 1,3-propanediol

E. coli

Similar unit operations

5 million pounds produced in one month at DTL BioProducts commercial

facility

Successful Collaborations Igene and Tate & Lyle: Astaxanthin

Igene had previously been tolling at large scale with another company

Tate & Lyle tech transferred/adapted the process to its UK-based citric

plant

Scale up did not work as planned

On-site parallel lab fermentors identified and resolved issues

Final plant performance exceeded previous lab fermentor performance

Future Successful Collaborations?

Industry has become highly specialized: no one “does it

all,” per se

Thank you for your attention!

Christopher J. Guske, Ph.D.

D2 Biotech Consulting, LLC

c.guske@Comcast.net

(217) 464-0898