fermentation 2 - genomatica€¢ methodical technology transfer • validate fermentation sterility...

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Biofuels Digest WebinarAdvanced FermentationJeff LievenseApril 12, 2016

FERMENTATION 2.0(CONTINUED)

• Scale-up case study: Genomatica’s 1,4-butanediol• Begin with the end in mind!• Methodical technology transfer• Validate fermentation sterility• A faster, better in-plant scale-up tool• Full-scale performance should be better than the lab• Bioengineering reference material

Jeff LievenseSenior Engineering Fellow

Genomatica: proven platform to “industrialize” biotechnologyBioengineering competencies across computation, experimentation, & bioprocessing, all tightly integrated

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optimizing cell factories

integrated process development & engineering

engineering enzyme component

high-fidelity scaling to commercial

Enabling Science& Industrialization

CommercialRealization

in silico pathway, process design & prototyping

guiding with techno-economics

Robust biobasedprocesses and solutions

systems bioengineering

optimalpathway

bank

Lab Pilot Demo Commercial$0

$250

$500

$750

$1,000

$1,250

$1,500

$1,750

$2,000

$2,250

$2,500

$2,750

0 500 1000 1500 2000 2500 3000 3500 4000

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ro

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ost,

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Scalable Engineering Designs & Development

Visualize & Validate Large-scale Outcome


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Genomatica’s Bioengineering Solutions businessGroup expansion, public announcement, April 2016, following first dozen projects

Biofuels Digest WebinarAdvanced FermentationApril 12, 2016Jeff Lievense

Process and Product Validation at Commercial Scale

50 fermentations run at commercial scale with integrated continuous downstream processing

No surprises - consistent performance, all scales 1st mass production and sale of an established

bulk industrial petrochemical by fermentation 2013 Kirkpatrick Chemical Engineering

Achievement Award

Scale-Up Partners:

5MM lbs5 Week Campaign

Demo

Pilot

Lab

30L 3,000L

13,000L

2009 2010 2011 2012

1,4-Butanediol case study: 5 years from concept to commercialProcess and product validation at commercial scale following extensive piloting

DuPont Tate & Lyle BioProducts 1,3-Propanediol Plant

Tate & Lyle Corn Processing PlantLoudon TN

600,000L


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1,4-Butanediol commercial scale performanceProcess robust, performed as planned, few surprises, performance upside

Robust Performance at Commercial-Scale

Fermentation performance at commercial-scale equivalent to demonstration-scale Low variability in fermentation performance indicates process robustness and predictability Top 5 commercial-scale fermentations indicate continuous improvement opportunity

Consistent Scale-up to Commercial

13,000L

Demonstration Scale

Commercial Scale

~ 50x scale-up

Campaign Strain

Titer 98%Rate 104%Yield 100%

Average Fermentation Performance

( ~50 runs at commercial scale vs. average demo scale)

0%

20%

40%

60%

80%

100%

120%

0 5 10 15 20 25 30 35 40 45 50Batch No.

Percent Average Commercial-Scale Yield

Top 5 Fermentation RunFermentation Run

5Biofuels Digest WebinarAdvanced FermentationApril 12, 2016Jeff Lievense

Safety as a priority Regulatory approvals Waste disposal addressed Detailed project management Communications and teamwork across

three companies Rigorous technology transfer Formal risk analysis and mitigations 100.0% reliable plant infrastructure Aseptic fermentation systems Experienced production team Validated process & product Validated local raw materials On-site R&D support Logistics and sales

Why Did it Work?

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Begin with the end in mind! Work backwards from large-scaleWhole process centric. Not microbe, process, or business case centric.


Susceptibility to contamination Microbe approvals, containment,

disposal, coproduct (Fed)batch or (semi)continuous Size and number Materials of construction, compatibility Raw materials and sterilization Broth properties (viscosity, foaming,

composition, DSP effects) Oxygen intensity, cooling mode Gas pressures Process controls (pH, temp, DO,

nutrients, foaming, VOCs) Mass and heat transfer Heterogeneous environment Capital and operating costs

Design Large Scale, Then Scale Down

Methodical technology transferFollow this deliberate process (“no surprises, boring is good”)

WE THEY

OUR PLACE

“They” saw how “We” did it

“They” believe that it works

THEIR PLACE

“We” saw how “They” repeated it

“We” and “They” know it works at

their place

• Shared responsibility (hand-offs)• Detailed written protocols (verbal)• People move between sites (fortresses)• Expect problems – prepare to troubleshoot (assume success)• Seamless transfer – over-prepared; boring is good! (shortcuts, drama)

Strong Collaboration!

WE THEY


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Validate fermentation systems sterilityMicrobial contamination can be completely prevented through proper design and diligent operation.

Plan for the worst (time, people) Microbiologist (scope & camera) Validate the lab before commissioning the plant Water leak testing Pressure hold testing (Snoop®) Sterilization temperature testing (Tempilstick®) Nutrient medium incubation testing (long holds,

transfers) Fail-safe validation (simulate power and steam

upsets) Re-validate after every failure Environmental monitoring

Leaks

Foreign Microbes

House-keepingSterility

Sterility Validation Strategy


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A faster, better in-plant scale-up toolParallel lab fermentors, indispensable for validation and troubleshooting

Lab ProdProtocol/Medium

Prod

LabLab Ctrl

Prod AI

Ino

culu

m

PL

LP PP

2 x 2 lab fermentor study quickly isolates root causes

LLProd Lab

Lab Prod

LL

PL

LP

PP

FS Failure

- - - - - Lab-to-lab transfer

+ - + - - Production media prep

+ + - - - Production inoculum

+ + + + - Full-scale environment

9Biofuels Digest WebinarAdvanced FermentationApril 12, 2016Jeff Lievense

Full scale performance should be better than the labApply simple tools for process learning, continuous improvement, and optimization

Use trend charts to visualize data through time• And talk to the plant operators

Use scatter plots to identify +/- outliers• And talk to the plant operators


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Bioengineering reference material: whole process thinkingBegin with end in mind; diligent in the 1000s of details; prepare for the unexpected

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Print publications• Design and Operating Principles for Bioprocess

Chemical Engineering, November 2015• Harnessing Biotechnology: A Practical Guide,

Chemical Engineering, April 2016• Technology Challenges and Opportunities in

Commercializing Industrial Biotechnology Chemical Engineering Progress, June 2016

Biofuels Digest Webinar Advanced Fermentation Jeff Lievense April 12, 2016

On-line publications• Successfully scaling up industrial fermentations of chemicals/fuels

2014 BIO World Congress on Industrial Biotechnology (May 2014, Philadelphia) http://www.biofuelsdigest.com/bdigest/2014/05/20/no-shortcuts-to-the-top-a-digest-special-report-on-scale-up-in-industrial-biotechnology

• Tech. Challenges & Opportunities in Commercializing Industrial Biotech. Society for Biological Engineering workshop (September 2015, San Diego) http:/www3.aiche.org/proceedings/Conference.aspx?ConflD=CIB-2015

…first licensee, back integrating

Novamont: biobased 1,4-butanediol plant allows vertical integrationWorld’s first GENO BDO™ plant in Italy, an existing bulk petrochemical becomes biobased

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BDO Product Storage

Pipe Racks

Distillation

Evaporation

• BDO for Mater-Bi product line

• fully funded by Novamont

• $100M in capital

• 30kta facility (expanded from 18kta)

• H2’16 start up

family of biodegradable & compostable bioplastics

Evaporation

Biofuels Digest Webinar Advanced Fermentation Jeff Lievense April 12, 2016

fermentation 2 - genomatica€¢ methodical technology transfer • validate fermentation sterility...

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