David Glass Regulatory Presentation and Case Study BIO Pac Rim Conference December 2013

David J. Glass, Ph.D.
D. Glass Associates, Inc.
BIO Pacific Rim Summit
December 10, 2013

Presentation Overview
 Overview: U.S. and international biotechnology

regulation
 EPA TSCA biotechnology regulation and its impact on
biofuel and bio-based chemical production
 Case Study: Joule Unlimited Technologies, Inc.: EPA
review of Microbial Commercial Activity Notice (MCAN)
for modified cyanobacteria for ethanol production


Overview of U.S. Biotechnology
Regulation
Environmental Protection Agency
 Microbial pesticides, plant pesticides.
 Engineered microorganisms used for other industrial

purposes.

 Modified microorganisms, algae for biofuel, bio-based chemical production

U.S. Department of Agriculture
 Transgenic plants, plant-produced industrial products.
 Transgenic feedstocks for fuel, chemical production

Food and Drug Administration
 Foods, feed, food additives, pharmaceuticals
 Microbial biomass used for animal feed

Overview: USDA Biotechnology
Regulations
 Regulations issued in 1987 (7 CFR Part 340) cover environmental

uses, interstate movement of “potential plant pests”.
 Historically, these rules have covered outdoor field trials or
commercial growth of transgenic plants in agriculture and
industrial/pharmaceutical production.
 Numerous field trials of transgenic energy crops have also taken
place under these regulations.
 Major USDA decisions (e.g. commercial approvals) require
environmental assessment for NEPA compliance.
 USDA rules would apply to transgenic plants, and possibly
open-pond uses of modified algae.

International Biotechnology Regulation
 European Union. Applicable national government approval would be

required under “Contained Use” Directive 2009/41/EC or “Environmental
Release” Directive 2001/18/EC.
 Canada. Industrial uses of modified organisms may fall under the New
Substances Notification regulations under the Canadian Environmental
Protection Act.
 Australia. Under the Gene Technology Act and its regulations, both
contained and non-contained uses of modified microorganisms would
require a license from the government.
 In many other countries, biotechnology laws are based on the principles of
the Cartagena Protocol on Biosafety, part of the Convention on Biological
Diversity.


International Biotechnology Regulation
Poster
presented at
ABS 2013: See
my Advanced
Biotechnology
for Biofuels
blog for more
details on
international
regulations.
(http://wp.me/
pKTxe-8a)


EPA TSCA Biotechnology Rule:
Overview
 Regulations under the Toxic Substances Control Act (TSCA) at 40

CFR Part 725 cover “new microorganisms” not regulated
elsewhere in the federal government.
 “New microorganisms” defined as “intergeneric”:
i.e., containing deliberate combinations of coding nucleic acids
from more than one taxonomic genus.
 Many recombinant microorganisms will not meet this
definition, and not be covered by these rules.
 Most research and pilot projects are not regulated if suitably
contained. Commercial use or importation requires 90 day
advance notification to EPA.

R&D (“Small Quantities”) Exemption
 R&D uses of “new microorganisms” may qualify for

exemption, if used “solely for R&D” in a suitably “contained
structure”.
 Applicant must adopt procedures at the facility for controlled
access, inactivation of wastes, emission controls, worker
notification.
 Exemption applies to R&D by for-profit entities, usually
including pilot plants.
 Open-pond algae reactors may not be judged to be “contained
structures”; non-contained uses may require EPA notification
and review via TERA process prior to commencement.

TSCA Experimental Release Applications
 TERA must be filed 60 days before proposed outdoor use.
 There have been 25 TERAs submitted since 1997 for

small-scale, outdoor R&D of engineered microorganisms.
All but 3 have been approved.
 These have included agricultural microorganisms,
microbes to be used for bioremediation or for detection
of hazardous contaminants in soil.
 No TERAs to date for fuel or chemical processes.
 TERAs would provide stepwise review for any proposed
uses of modified algae in open ponds.

EPA TSCA Biotechnology Rule: Microbial
Commercial Activity Notices (MCANs)
 Commercial use or importation of “new microorganisms”

requires MCAN reporting at least 90 days before commencing
commercialization or importing microbe.
 MCAN requires submission of data to EPA.
 Microorganism identity, construction and properties.
 Potential health and environmental effects.
 Information about the industrial
process, control/containment measures, worker
exposure, possible environmental release.
 EPA review, clearance of MCAN authorizes commercial use.

Biofuel, Bio-Based Chemical MCANs
Over 50 MCANs reviewed since 1997, including:
 Numerous MCANs for industrial enzymes (most using
Trichoderma reesei as host organism).
 Several MCANs for production of ethanol from species including
E. coli, Klebsiella oxytoca, S. cerevisiae, Z. mobilis.
 MCANs for production of various bio-based chemicals.
 MCAN filing activity has significantly increased in the last several
years: at least 6-8 filings per year in FY 2011, 2012, 2013.


A Novel Gas-to-Liquid Platform
Powered by Sunlight, Fed by CO2, and Tailored for Valuable Products

©2013 Joule. Rights Reserved. Proprietary & Confidential.

www.jouleunlimited.com

A direct, continuous process with abundant inputs and valuable outputs
Our “upstream” platform converts CO2 to liquid fuels and chemicals, avoiding the extreme costs and risks of oil E&P

Programmable Biocatalyst

H2O

CO2

Ethanol

Diesel

Jet Fuel

Proprietary System

Gasoline

Efficient Process
©2013 Joule. Rights Reserved.

Chemicals
16


Our CO2 gas-to-liquids platform
The biocatalyst, production unit and infrastructure are engineered for high productivity and scalability
Programmable Biocatalyst
Novel Production Unit
Infrastructure

 The biocatalyst requires minimal
days of growth before diverting
its energy to fuel production
 Waste CO2 is biocatalytically
converted to targeted molecules
via photosynthesis


 The process inputs are
abundant, and the outputs can
be tailored by switching the
product-specific biocatalyst
 Production is readily scalable via
simple replication of modular
units

17

 The facility supports an
integrated production
process, from biocatalyst
construction
to product creation, separation
and storage
 The CO2 gas-to-liquid process is
direct and continuous

Joule SunSpringsTM Hobbs: Where the vision becomes reality

Biocatalyst Prep

Production Unit

 Commissioned in September 2012 to
test and demonstrate the platform at
increasingly larger scale
Central Plant

 Core production unit and
infrastructure in place to advance to
full process demonstration
 Achieving progress on numerous
variables, e.g. productivity, process
efficiency
 Sustained Sunflow®-E ethanol
production, with other products to
follow
 Facility and processes will become the
blueprint for future commercial plants


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EPA Jurisdiction over Joule’s production organisms
 Joule’s modified biocatalysts for ethanol production are
considered “new microorganisms” under EPA’s TSCA
biotechnology regulations (40 CFR Part 725):



The modified organisms include coding sequences from outside the
Synechococcus genus and are considered “intergeneric”.
The intended commercial use is for a purpose not regulated by any other
federal agency.

 First biocatalyst: modified strain of the cyanobacterium
Synechococcus for ethanol production.
 Laboratory, pilot and some demo plant activities qualify for the
“contained structure” (R&D) exemption.

 Commercial use requires filing a Microbial Commercial Activity
Notice (MCAN) at least 90 days before commercial use.

19


Joule Regulatory Strategy and Timeline
 Plan was to file first MCAN well in advance of anticipated start of
commercial use.
 Early presubmission meeting with EPA staff (2011).
 First MCAN for commercial ethanol production strain (MCAN
Number J12-0006) filed July 2012.
 Short-term goal was to gain approval to use this strain
commercially at Joule’s Demonstration Plant in Hobbs, New
Mexico.
 EPA completed its review Fall 2012, began drafting Consent Order
that would allow use of strain at Hobbs under specified conditions.

 Consent Order signed July 2013.


20


Data Included in MCAN
In the MCAN, Joule provided all available information to enable a risk
assessment for the MCAN biocatalyst strain, including:
 Description of strain construction.
 Biological characteristics of the MCAN strain.
 Genomic analysis and literature review to establish lack of evidence that
the Joule host strain has any toxic, infectious, or pathogenic properties.
 Review of literature data on natural habitats and environmental
incidence of the host strain.
 Discussion of ecology, geology of Hobbs site as they relate to
environmental impacts: e.g. local wildlife and flora, depth of aquifer.
 Data on survival/persistence in Hobbs soil.
 Description of Joule’s bioreactors, production process and containment
features.

21


EPA Conclusions
 Use of the strain at Hobbs is unlikely to present unreasonable risk.
 Minimal concerns for adverse human health effects, and minimal
concerns for ecological effects from use in ethanol production.
 The introduced genes are not inherently hazardous; probability of
horizontal gene transfer is expected to be low.
 Survival of the MCAN strain in Hobbs soil is expected to be low in
the event of breach of containment.
 However, these findings cannot (yet) be extended to locations
other than Hobbs, e.g. pending data on MCAN strain survival in
other environments; so EPA required Joule to enter into a Consent
Order limiting approved uses to Hobbs.
 Certain testing and data are required to allow an assessment of
commercial use at sites other than Hobbs.

22


Summary: Consent Order Requirements
 Commercial Use of MCAN Strain at Hobbs is allowed, subject to
terms of the Consent Order.
 Soil Survival Testing. Conduct additional studies of the
survivability of the MCAN strain in Hobbs soil, using an EPAapproved protocol within one year of commencing commercial
use of the MCAN strain at Hobbs.
 Validation of Waste Inactivation. During first year of use of the
MCAN strain, monitor the efficacy of the waste inactivation
system, using EPA-approved protocol, to show 6-log reduction.
 Monitoring of Capsule Failures. Required to keep appropriate
records of capsule breaches and accidental spills, and to keep
records documenting how these releases were cleaned up.
Records to be available for EPA review upon request.

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Summary
 Joule’s goal achieved to enable use of the MCAN strain at Hobbs.
 First MCAN established that EPA had minimal concerns over
potential health or safety impact of Joule’s production organisms.
 EPA review identified key data and information to include in future
MCAN submissions; particularly data needed to support use at
facilities other than Hobbs.

 Joule has developed a productive relationship with EPA staff.
 Reviews of future Joule MCANs for additional ethanol production
organisms should be quicker, more straightforward.
 Successful EPA review of first MCAN may be useful in dealings with
regulatory bodies in other countries.


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Thank you very much
David J. Glass, Ph.D.
124 Bird Street
Needham, MA 02492
Phone 617-653-9945
dglass@dglassassociates.com
www.dglassassociates.com


David Glass Regulatory Presentation and Case Study BIO Pac Rim Conference December 2013

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