Several previous entries in this blog from 2010 (beginning here), described U.S. Environmental Protection Agency (EPA) regulations under the Toxic Substances Control Act (TSCA) that may cover the use of certain genetically modified microorganisms in biofuel or bio-based chemical production. In one of these posts, I briefly listed and summarized several MCANs that had been filed up to that point, covering novel microorganisms intended for use in fuel production, as well as those covering microbes engineered to produce novel enzymes. In today’s entry, I’ll cover the several additional biofuel-related MCANs that, since the time of my earlier posts in May 2010, have been listed on EPA’s website as having been filed and reviewed by the agency.
To summarize the prior entries, the TSCA Biotech Rule covers certain modified microorganisms, specifically those containing deliberate combinations of coding nucleic acids derived from more than one taxonomic genus, but only when those organisms are used for commercial purposes not regulated by other federal agencies. The use of microorganisms or algae to produce ethanol, butanol, biodiesel or other biofuels is an industrial application that would almost certainly fall under TSCA jurisdiction. However, microbial strains that are modifications of certain common industrial organisms such as E. coli or S. cerevisiae might qualify for exemptions under these rules. For those modified microorganisms falling under the rules, most R&D uses (including activities at pilot plants) would probably be exempt, but applicants contemplating commercial use of a covered microorganism must notify EPA at least 90 days before commencing manufacture or import, filing a notification document called a Microbial Commercial Activity Notice (MCAN).
EPA has been receiving MCANs and other notifications of biotechnology products under its interim TSCA policy since 1987 and under the current rules since 1997, and these regulations have not proven to be a barrier to industrial biotechnology companies, including those developing biofuel products or processes. Most of the notifications EPA has received have been for uses of intergeneric microorganisms to manufacture industrial enzymes and specialty chemicals. Many of these, particularly in recent years, have been for enzymes intended for use in the production of cellulosic ethanol or other biofuels. My earlier blog post summarized those that had been filed through 2009. The following MCANs for enzyme production have been received from 2010 to date (note that these MCANs likely cover the production organisms for recent enzyme products for use in ethanol production that have been released by DuPont Danisco and Novozymes):
- Danisco US, Inc., MCAN J10-0002. Trichoderma reesei modified to produce enzymes for ethanol production. Received November 2, 2009. Notice of Commencement filed October 20, 2010.
- Danisco US, Inc., MCAN J10-0003. Trichoderma reesei strain 3408 to produce enzymes for ethanol production. Received June 3, 2010. Notice of Commencement filed October 20, 2010.
- Danisco US, Inc., MCAN J11-0004. Trichoderma reesei strain modified to produce the new microorganism T. reesei 3417, used to produce a (hemi)cellulase enzyme complex for biofuel production from cellulosic biomass. Received April 14, 2011. Notice of Commencement filed March 10, 2012.
- Novozymes North America, Inc., MCAN J11-0005. Modified strain of Trichoderma reesei to produce a cellulolytic protein preparation to be used for ethanol production. Received August 4, 2011. Notice of Commencement filed July 19, 2012.
- Novozymes North America, Inc., MCAN J11-0006. Modified strain of Trichoderma reesei for the biosynthesis of cellulose-degrading enzymes to be used for ethanol production. Received August 15, 2011. Notice of Commencement filed July 19, 2012.
EPA has also received MCAN filings for genetically modified microorganisms where the organism itself is designed for use in production of ethanol or other fuels. The following are the MCANs filed since 2010 listed on the EPA website that cover such production organisms .
- Verenium Corporation. MCAN J10-0001. Modified Escherichia coli W-BD28512, to be used to ferment C5 sugars from lignocellulosic biomass to ethanol. Received October 1, 2009. This is an E. coli strain that features further modifications of the intergeneric strain BD26981, that was the subject of an earlier MCAN from this company (MCAN J08-0001). The modifications included the addition of one intergeneric coding sequence (identity claimed as confidential) and the deletion of the methylglyoxal synthase gene (mgsA). These modifications were made to improve the ethanol production capability of the original intergeneric strain.
- Company confidential. MCAN J11-0001. Saccharomyces cerevisiae strain modified for use in ethanol production. Received October 26, 2010. All details of the modification of this strain have been claimed as confidential, along with the identity of the applicant.
- E. I. du Pont de Nemours and Company. MCAN J12-0002. Z. mobilis ZM4, modified to produce the new organism Z. mobilis XA111, that will be able to utilize both xylose and arabinose in ethanol producing fermentation processes. Received December 6, 2011. The microorganism that is the subject of this MCAN is related to a microbial strain that was the subject of a previous DuPont MCAN (MCAN J09-0003), in that both strains were derived from the same starting point, the wild type Z. mobilis strain ZM4. The original intergeneric strain was capable of producing ethanol from xylose substrates, and the new strain, created through modifications claimed as confidential, can now utilize either xylose or arabinose sugars as substrate.
- Company confidential. MCAN J12-0004. Saccharomyces cerevisiae strain modified for use in ethanol production. Received April 26, 2012. All details of the modification of this strain have been claimed as confidential, along with the identity of the applicant.
- Lallemand Specialties, Inc. MCAN J12-0005. Saccharomyces cerevisiae strain modified for use in ethanol production. Received May 22, 2012. All details of the modification of this strain have been claimed as confidential. Although the applicant company Lallemand is now identified on the EPA website, the company’s name was originally claimed as confidential.
A few interesting trends can be seen in these new MCAN filings for ethanol production organisms. Two of these, MCAN J10-0001 and MCAN J12-0002, are from companies that had previously filed MCANs for other cellulosic ethanol production strains, and these new filings cover newly-engineered microorganisms with enhanced or expanded properties. The other three filings are all for modified yeast strains with improved ability to produce ethanol. These are of interest because many modified strains of S. cerevisiae could qualify for the tiered exemptions available under the TSCA biotechnology rule and would therefore not need MCAN filings. The likeliest reason that these companies decided to fie MCANs rather than rely on the exemptions was to facilitate the use of the strains by third parties such as partners or licensees – in fact this rationale is mentioned in at least one of the MCANs, MCAN J11-0001. Once an MCAN for a new microbe is cleared by EPA, the applicant and any third party can use the new microbe for any purpose under any conditions, whereas the Tier I and Tier II exemptions require users of the microorganism either to adhere to strict containment conditions (under the Tier I exemption) or obtain EPA approval of containment provisions (under Tier II). As more technology developers adopt licensing as a business model, I expect we’ll see an increasing number of MCANs filed for this reason, to facilitate third party use, even for microorganisms that might otherwise be eligible for an exemption.
Note that MCANs are reviewed by EPA, but no formal “approval” is needed. If the Agency does not identify any unusual risks or any reason to extend its review during the 90 day review period, the MCAN is deemed to be cleared (or “dropped from review” in the terminology used at the EPA website) and the applicant can proceed to commercialization. All of the above MCANs have been dropped from review without Agency action, except for MCAN J10-0002, which was dropped from review subject to a Significant New Use Regulation (SNUR) applied to this organism by EPA – an agency action which I’ll describe in a later blog post. Once an MCAN is dropped from review, applicants must submit a Notice of Commencement when commercial use (or importation) of the subject microorganism is to begin, and as can be seen from the above, not all of the microorganisms covered by these MCANs have yet progressed to commercial use.
D. Glass Associates, Inc. is a consulting company specializing in government and regulatory support for renewable fuels and industrial biotechnology. David Glass, Ph.D. is a veteran of over thirty years in the biotechnology industry, with expertise in industrial biotechnology regulatory affairs, U.S. and international renewable fuels regulation, patents, technology licensing, and market and technology assessments. Dr. Glass also serves as director of regulatory affairs for Joule Unlimited Technologies, Inc. More information on D. Glass Associates’ regulatory affairs consulting capabilities, and copies of some of Dr. Glass’s prior presentations on biofuels and biotechnology regulation, are available at www.slideshare.net/djglass99 and at www.dglassassociates.com. The views expressed in this blog are those of Dr. Glass and D. Glass Associates and do not represent the views of Joule Unlimited Technologies, Inc. or any other organization with which Dr. Glass is affiliated. Please visit our other blog, Biofuel Policy Watch.