Simplifying Regulatory Approvals for Genetically Modified Yeast in

Distillers Co-ProductsDavid J. Glass, Ph.D.

D. Glass Associates, Inc.Fuel Ethanol Workshop

June 21, 2016

∗ Over 43 million tons of DDGS produced in the U.S. in 2013-2014 (approx. 33 million used domestically, 10 million exported)1.

∗ Approximately 98% of the distillers grains used in North America are a byproduct of fuel ethanol production2.

1. Source: Iowa State University. http://www.extension.iastate.edu/agdm/crops/outlook/dgsbalancesheet.pdf2. Source: University of Minnesota, Distillers Grains By-products in Livestock and Poultry Feeds, 2007 , cited on FDA website, http://www.fda.gov/AnimalVeterinary/Products/AnimalFoodFeeds/Contaminants/ucm190907.htm

Distillers Co-Products

Use of Modified Yeast Strains in Distillers Co-Products

∗ Growth in the U.S. ethanol industry has Increased interest in the development of modified yeast strains to improve ethanol production.

∗ This has led to increased interest in the use of modified yeast strains in distillers co-products.

Researchers are modifying S. cerevisiae in several ways to improve ethanol production:∗ Express enzymes to improve feedstock processing.∗ Impart new pathways to utilize C5 sugars,

e.g. from cellulosic feedstocks.∗ Metabolic engineering to reduce byproducts

like glycerol.∗ Improve ethanol tolerance of strains.

Modified Yeast Strains to Improve Ethanol Production

∗ Industrial use of modified yeast strains is regulated by EPA under its TSCA biotechnology rules.

∗ Although some uses are exempt, there have been at least 27 Microbial Commercial Activity Notices reviewed and cleared by EPA for different modified S. cerevisiae strains1.

∗ Use of GMO Yeast in DDGs regulated as Animal Feed Ingredients.

1. Source: https://www.epa.gov/regulation-biotechnology-under-tsca-and-fifra/tsca-biotechnology-notifications-status

Regulation of Industrial Use of Modified Yeast Strains

∗ FDA regulates food and feed.∗ Manufacturers must not introduce foods that are

adulterated.∗ Ingredients that have not been used in food are

considered “additives” and must be reviewed for safety and efficacy.

∗ Certain products, like traditional DDGs,considered GRAS due to long history of use;others can achieve GRAS status as well.

U.S. Regulation of Animal Feed Ingredients

FDA Biotechnology policy is not clear on the extent of genetic changes to an organism that would trigger need for new review.

FDA Genetic Engineering Policy

Comments questioned whether a substance (including microbes) that is GRAS could lose its GRAS status solely because it was produced or modified by new biotechnology. The answer is yes, if the substance (and its contaminants) has been altered in such a way that it can no longer be generally recognized by qualified experts to be safe. In this instance, the substance would be a food additive.

Source: FDA Statement in Coordinated Framework for Biotechnology Regulation, 1986

Although overseen by FDA CVM there are several options for approval of new feed ingredient:∗ GRAS Self-determination∗ GRAS Self-determination, notification to FDA∗ FDA Feed Additive Petition∗ AAFCO New Ingredient Definition

U.S. Regulation of Animal Feed Ingredients

Different Paths to Approval

∗ The different pathways all generally require the same types of data.

∗ Manufacturing Chemistry; Analytical Methods∗ Identity∗ Manufacturing process and controls∗ Product specifications∗ Stability (product and in feed)∗ Analytical methods: product, quantification in feed

∗ Utility∗ Intended Use∗ Feeding studies to show efficacy?

∗ Safety∗ Target Animal – white paper or studies∗ Human food -- Toxicology and Residue Chemistry – white paper or studies ∗ Environmental – Assessment or Categorical Exclusion

Adapted from K. Smedley presentation at 2016 AAFCO Midyear Meeting, January 2016

Data Requirements for FDA, AAFCO Approval Pathways

Different Paths to Approval

∗ The different pathways all generally require the same types of data.

∗ The same group at FDA CVM conducts the technical review under all the pathways.

∗ There are pros and cons to each approach, but –∗ The track record to date for approvals of modified

yeast strains has been very limited.

∗ Under U.S. law, a product for use in food or feed can be determined to have GRAS status in two ways:∗ Experience based on common use in food or feed or∗ “Scientific principles” – that, based on publicly available

information, there is a consensus among qualified experts that those data and information establish that the substance is safe under the conditions of its intended use

∗ A manufacturer can make such determinations itself, usually based on the advice of an expert scientific panel.

GRAS Self-Determination

∗ Established 2010, modeled after successful program for GRAS substances in human food.

∗ Applicant makes its own GRAS determination, submits dossier to obtain FDA concurrence.

∗ FDA responds either “no questions” or “does not support GRAS status”.

∗ To date, 20 submissions, only 7 of which received favorable “FDA has no questions” ruling.

FDA CVM GRAS Notification Program

GRAS Notification Process: No Successful Yeast Strain Requests

Submitter Product Purpose StatusGevo Inactivated

modified S. cerevisiae

Component of animal feed when used in the fermentation and distillation of corn to produce isobutanol

Notice does not provide a basis for a GRAS determination

Gevo Isobutanol distillers grain

Component of animal feed At notifier's request, FDA ceased to evaluate the notice

DSM Inactivated modified S. cerevisiae

Component of animal feed when used in the fermentation of corn to produce ethanol

At notifier's request, FDA ceased to evaluate the notice (Resubmitted 4/29/16, pending)

http://www.fda.gov/AnimalVeterinary/Products/AnimalFoodFeeds/GenerallyRecognizedasSafeGRASNotifications/ucm243845.htm

∗ AAFCO established a process to add approved new ingredient definitions to their Official Publication.

∗ Applicants submit dossier to AAFCO Investigator, for review by FDA CVM.

∗ New definitions approved by Ingredient Definition Committee and full AAFCO membership.

AAFCO New Ingredient Definition Process

AAFCO: Association of American Feed Control Officials

Successful AAFCO Requests for Novel Yeast Strains

Source: 2016 AAFCO Official Publication, pp. 443-444.

AAFCO Process is manageable but time-consuming

12-18 mos 3-6 mos 6 mos 12 mos minimum

Submission

CVM Review

CVM Letter

AAFCO Ingredients Definition Cmte Vote

Good case scenario: 36 months from submission to publication

Biannual meeting cycle Annual publication cycle

CVM & AAFCO MOU: The 2 organizations work together under a Memorandum of Understanding that currently expires Sept 2017

Publication in the “next” Official

Publication

AAFCO General Membership

Vote

Slide courtesy of Kevin Wenger, Mascoma/Lallemand, used with permission

Pros Cons

GRAS Self-determination Does not require agency review

Not recognized by many states, Canada

GRAS Notification throughFDA

When successful, GRAS status clearly established

Program has not workedwell, especially for biotech products

Feed Additive Petition through FDA

If approved, legal status clear at FDA and AAFCO

Time-consuming, requires rule-making, no precedent for yeast

AAFCO IngredientDefinition

Iterative review process, approval clears marketing in all states

Time-consuming, dependent upon AAFCO meeting schedule

Different Paths to Approval

∗ For modifications to microorganisms with a long history of use in food and feed, including Saccharomyces cerevisiae yeast, why should animal feeding studies be needed to show safety?

∗ Shouldn’t comparison to naturally-occurring species (or ingredient containing naturally-occurring organism) be sufficient?

∗ A better model is the Voluntary Consultation program in place since 1996 for GMO crop plants.

Use in Feed of Yeast and other Familiar Microorganisms

∗ Limited to plant species: microorganisms excluded by definition.

∗ Process:∗ Initial consultations.∗ Submission of company’s safety

and nutritional assessment.∗ Review by Biotechnology Evaluation

Team with members from FDA CFSAN and CVM.

∗ FDA may request a meeting, or submission of more data.

FDA Voluntary Consultation for GMO Crops

∗ FDA may conclude: ∗ No further questions ∗ The product requires review as

a food additive∗ There are other regulatory issues

(e.g. labeling requirements) to be addressed.

∗ Consent given to > 170 cases to date.∗ Average time to decision has been

increasing over time, but is approximately 20-24 months.

FDA Voluntary Consultation for GMO Crops

Adapting the Voluntary Consultation Process for Microorganisms (1)

FDA Voluntary Consultation Program Proposed New Process

The name of the bioengineered food and the crop from which it is derived.

The name of the modified feed ingredient and the microbial species from which it is derived, including documentation of taxonomy.

A description of the various applications or uses of the bioengineered food, including animal feed uses.

A description of the applications or uses of the modified feed ingredient in animal feed, including any use limitations, and the identity of the target animal species. Identification of current or prior uses of the selected microbial species in animal feed, to which the proposed use(s) can be compared.

Information concerning the sources, identities, and functions of introduced genetic material.

Information concerning the sources, identities, and functions of introduced genetic material.

Information on the purpose or intended technical effect of the modification, and its expected effect on the composition or characteristic properties of the food or feed.

Information on the purpose or intended technical effect of the modification, and its expected effect on the composition or characteristic properties of the modified feed ingredient derived from the modified microorganism.

Adapting the Voluntary Consultation Process for Microorganisms (1)

FDA Voluntary Consultation Program Proposed New Process

The name of the bioengineered food and the crop from which it is derived.

The name of the modified feed ingredient and the microbial species from which it is derived, including documentation of taxonomy.

A description of the various applications or uses of the bioengineered food, including animal feed uses.

A description of the applications or uses of the modified feed ingredient in animal feed, including any use limitations, and the identity of the target animal species. Identification of current or prior uses of the selected microbial species in animal feed, to which the proposed use(s) can be compared.

Information concerning the sources, identities, and functions of introduced genetic material.

Information concerning the sources, identities, and functions of introduced genetic material.

Information on the purpose or intended technical effect of the modification, and its expected effect on the composition or characteristic properties of the food or feed.

Information on the purpose or intended technical effect of the modification, and its expected effect on the composition or characteristic properties of the modified feed ingredient derived from the modified microorganism.

Adapting the Voluntary Consultation Process for Microorganisms (2)

FDA Voluntary Consultation Program Proposed New Process

Information concerning the identity and function of expression products encoded by the introduced genetic material, including an estimate of the concentration of any expression product in the bioengineered crop or food derived thereof.

Information concerning the identity and function of expression products encoded by the introduced genetic material, including an estimate of the concentration of any expression product in the modified feed ingredient.General description of the manufacturing process of the modified feed ingredients.

Information regarding any known or suspected allergenicity and toxicity of expression products and the basis for concluding that foods containing the expression products can be safely consumed.

Information regarding any known or suspected allergenicity**, pathogenicity or toxicity of expression products and the basis for concluding that modified feed ingredients containing the expression products can be safely consumed.

Information comparing the composition or characteristics of the bioengineered food to that of food derived from the parental variety or other commonly consumed varieties with special emphasis on important nutrients, and toxicants that occur naturally in the food.

Information comparing the composition or characteristics of the modified feed ingredient to that of an ingredient derived from the parental species or other commonly utilized wild type strains or species with special emphasis on important nutrients, and toxicants that occur naturally in the feed product.

**References to allergenicity would likely be relevant only for ingredients intended for food-producing animals.

Adapting the Voluntary Consultation Process for Microorganisms (2)

FDA Voluntary Consultation Program Proposed New Process

Information concerning the identity and function of expression products encoded by the introduced genetic material, including an estimate of the concentration of any expression product in the bioengineered crop or food derived thereof.

Information concerning the identity and function of expression products encoded by the introduced genetic material, including an estimate of the concentration of any expression product in the modified feed ingredient.General description of the manufacturing process of the modified feed ingredients.

Information regarding any known or suspected allergenicity and toxicity of expression products and the basis for concluding that foods containing the expression products can be safely consumed.

Information regarding any known or suspected allergenicity**, pathogenicity or toxicity of expression products and the basis for concluding that modified feed ingredients containing the expression products can be safely consumed.

Information comparing the composition or characteristics of the bioengineered food to that of food derived from the parental variety or other commonly consumed varieties with special emphasis on important nutrients, and toxicants that occur naturally in the food.

Information comparing the composition or characteristics of the modified feed ingredient to that of an ingredient derived from the parental species or other commonly utilized wild type strains or species with special emphasis on important nutrients, and toxicants that occur naturally in the feed product.

**References to allergenicity would likely be relevant only for ingredients intended for food-producing animals.

Adapting the Voluntary Consultation Process for Microorganisms (3)

FDA Voluntary Consultation Program Proposed New Process

A discussion of the available information that addresses whether the potential for the bioengineered food to induce an allergic response has been altered by the genetic modification.

A discussion of the available information that addresses whether the potential for the modified feed ingredient to induce an allergic response** has been altered by the genetic modification.

Any other information relevant to the safety and nutritional assessment of the bioengineered food.

Any other information relevant to the safety and nutritional assessment of the modified feed ingredient, including any information inconsistent with the determination of safety.Other information needed for AAFCO purposes, including: proposed Feed Ingredient Definition and proposed label, etc.

Other information needed for GRAS purposes, including proposed GRAS claim, basis for concluding GRAS status, etc.

Adapting the Voluntary Consultation Process for Microorganisms (3)

FDA Voluntary Consultation Program Proposed New Process

A discussion of the available information that addresses whether the potential for the bioengineered food to induce an allergic response has been altered by the genetic modification.

A discussion of the available information that addresses whether the potential for the modified feed ingredient to induce an allergic response** has been altered by the genetic modification.

Any other information relevant to the safety and nutritional assessment of the bioengineered food.

Any other information relevant to the safety and nutritional assessment of the modified feed ingredient, including any information inconsistent with the determination of safety.Other information needed for AAFCO purposes, including: proposed Feed Ingredient Definition and proposed label, etc.

Other information needed for GRAS purposes, including proposed GRAS claim, basis for concluding GRAS status, etc.

∗ A quicker procedure for approval of modified strains of common food/feed microorganisms is needed, particularly for use of yeast in DDGs, where there is such a long history.

∗ For familiar microbial species, comparison of the modified strain to wild-type should be sufficient to assess safety and avoid the need for feeding studies.

∗ However, staffing issues at FDA CVM will continue to be the bottleneck for all technical reviews of new feed ingredients.

∗ Can this procedure be adopted as part of ongoing “modernization” of the Coordinated Framework?

Conclusions

David J. Glass, Ph.D.D. Glass Associates, Inc.124 Bird StreetNeedham, MA 02492 USAPhone 617-653-9945dglass@dglassassociates.comwww.dglassassociates.com

More details on this proposal in Advanced Biotechnology for Biofuels blog: http://wp.me/pKTxe-cn

Thank you!