FDA Regulation of Biofuel Production Microorganisms Used in Animal Feed

In a previous post on this blog, back in June 2010, I posted a brief discussion of the regulations of the U.S. Food and Drug Administration governing animal feed and feed additives, as they may impact the use of spent microbial biomass from biofuel fermentations in animal feed. It has been frequent practice for years to use such microbial biomass (which most often comprised common yeast strains) as a component of dried distillers grains or other products used as animal feed, and many companies developing genetically modified yeast strains or other microorganisms for use in ethanol fermentations are investigating how their strains, once inactivated after fermentation, can be used for this purpose. In this post, I’d like to go into a little more detail about the FDA regulatory structure under which such uses would be reviewed and approved in the United States.

The use of spent biomass in animal feed, or to produce a substance to be used in animal feed, would be regulated in the U.S. by the Food and Drug Administration. FDA regulation of animal feed is not much different from its regulation of human food, especially for feed intended for use in food-producing animals. Specifically (and contrary to popular belief), FDA does not regulate “food” per se: whole food products are presumed to be safe for consumption, but FDA has enforcement powers to be sure marketed food products are not adulterated. So, FDA regulation is largely directed at new substances proposed for use as human food additives or as animal feed additives. Under the Federal Food, Drug and Cosmetic Act, most such new substances that are intended to be components of food or to affect components of food are considered to be “food additives” and must be approved through the submission of a Food Additive Petition or, in the case of products for animal consumption, “feed additives” requiring Feed Additive Petitions. Food or Feed Additive Petitions generally rely on manufacturer-generated data on the manufacture, composition and safety of the additive, and usually include toxicology testing.  FDA must undertake formal rulemaking to grant approval of a food additive petition.

The law further provides that “substances that are generally recognized, among experts qualified by scientific training and experience to evaluate their safety as having been adequately shown …  to be safe under the conditions of their intended use,” are not considered as food additives. This created the category of substances known as GRAS: “generally recognized as safe”. Certain substances were “grandfathered” in as GRAS at the time of the legislation based on common prior safe use in foods, other GRAS substances were later affirmed by FDA to be GRAS, often in response to manufacturer petitions, under a petition process established in the regulations (21 CFR Part 170.35 for human food and Part 570.35 for animals). These GRAS affirmations were generally based on scientific information in the public domain. It is important to point out that GRAS determinations are not made for the substance per se, but for the substance in its intended use, so that a substance might be GRAS for one food use but not for another.

By 1997 FDA concluded that it could no longer devote substantial resources to the GRAS affirmation petition process. On April 17, 1997, the agency published a proposed rule outlining a GRAS notification process for both human and animal foods to replace the petition process.  Under the new proposal, applicants would submit notifications containing data that supports their own determination that a substance should be considered as GRAS. The FDA would review the notification and either accept the determination based on the applicant’s data, or request further data. The agency also announced that its Office of Food Additive Safety would immediately institute the human food notification scheme as a pilot program, and that it would accept and administer GRAS notices as described in the proposed rule until a final rule was published. To date, a final rule has not yet been issued, but FDA has been operating the human food notification program as an interim policy since 1997. The FDA website describes the pilot program for human GRAS notifications.

The 1997 notice did not originally extend the pilot program to animal feed substances, but on June 4, 2010, the Agency announced the creation of an animal feed GRAS pilot program, to be administered by the FDA’s Center for Veterinary Medicine (CVM). The program for animal feeds is described on the website, and like the human program, it now allows applicants (called “notifiers”) to submit notifications in which they inform the Agency that they believe an animal feed substance qualifies for GRAS status. The website gives the following guidance for the information that should be included in the notification.

[Notifications should provide] a succinct description of the substance, the applicable conditions of use, and the basis for the GRAS determination (scientific procedures or common use in food). The applicable conditions of use of the substance include the foods in which the substance is to be used, levels of use in such foods, the purposes for which the substance is used, and the specific animal species intended to consume the substance. If the intended use of the substance includes administration to food-producing animals, a human food safety component must be included.  The notice should also include information about the identity and properties of the substance and a discussion of the notifier’s reasons for concluding that the substance is GRAS for its intended use. The information about the substance generally is chemical, toxicological, and, if applicable, microbiological in nature. The notifier should discuss information supporting the GRAS determination, as well as any information that would appear to be inconsistent with a GRAS determination, and explain why, in light of the totality of the information, the notifier concludes the substance is GRAS under the intended conditions of use.

In the animal feed GRAS program, FDA CVM evaluates whether the notice provides a sufficient basis to support a GRAS determination or instead whether information in the notice, or information otherwise available, raises issues that might question the GRAS status of the proposed use. The Agency issues an opinion letter at the end of its review, and for those notifications that it clears for commercialization, the Agency’s letter says it has “no questions” about the applicant’s determination of GRAS status but states that FDA is not making its own determination. Alternatively, the letter may state the Agency’s conclusion that the notice does not provide a sufficient basis for a GRAS determination (e.g., because the notice does not include appropriate data and information, or because the available data and information raise questions about the safety of the substance).

Since implementing these policies, FDA has maintained inventories of received and pending GRAS notices. The human product inventory includes well over 400 entries (about two dozen of which appear to be pending at any given time). The inventory for animal feed GRAS notices is much smaller, since it lists only those notices received since the pilot program began in 2010. At this writing, there are 14 entries on the animal product inventory, and only 3 of these have been approved (i.e. these applications received FDA’s determination that they had “no questions”). Of the ones not approved, a few were withdrawn by the submitter while others bear the notation “Notice does not provide a basis for a GRAS determination”. Two of the rejected notices and the one that is still pending appear to cover products derived from recombinant microorganisms. Nonconfidential versions of the non-withdrawn notices, and FDA’s decision letters for each, can be downloaded from the inventory site.

Because, historically, the microorganisms used to produce fuel ethanol have been yeasts or other well-known species, companies seeking approval to sell the spent biomass for animal feed have contemplated the GRAS route, but in principle the feed additive process could also apply. The GRAS process is usually considered to be less burdensome than the food or feed additive petition process (this is certainly the case for human food additives) and so that is another reason the GRAS route might be favored.

Although the law and regulations give FDA the ultimate authority to make decisions on food or feed additive petitions and GRAS determinations, in practice CVM operates in cooperation with the Association of American Feed Control Officials (AAFCO), which is composed of state, federal, and international regulatory officials who are responsible for the enforcement of state laws regulating the safe production and labeling of animal feed. According to FDA’s website, FDA and AAFCO work together on animal feed regulation, particularly in the establishment of definitions to describe new feed ingredients. Each year AAFCO publishes its Official Publication which includes a model feed bill for states to adopt in regulating feed products and a list of accepted feed ingredients. Most states have adopted all or part of the model feed bill and allow feed ingredients listed in the publication to be used in their respective territories.

FDA and AAFCO entered into a memorandum of understanding in 2007, which was renewed in 2012, which specifies how these organizations would work together on animal feed regulation, allows FDA to formally recognize AAFCO’s list of feed ingredients, and defines the role FDA can play in deciding on the suitability of feed ingredients proposed for addition to the list. In practice, CVM assigns scientists to work with AAFCO in reviewing petitions for new feed ingredients, and this cooperation includes both GRAS petitions and feed additive petitions. AAFCO uses a “New and Modified Feed Ingredient Definitions Process” to determine the suitability of feed ingredients and to establish standard ingredient names, which FDA considers the common or usual name, used on feed labels as required by state and federal law. In addition, before it adopts a new feed ingredient definition or amends an existing one, AAFCO will ask CVM for advice and a letter of concurrence.

There appears to only be one genetically modified biofuel production microorganism that has cleared the FDA/AAFCO process to achieve GRAS status, although it is not listed on the FDA website inventory. This is a genetically modified yeast strain developed by Mascoma Corporation. Mascoma announced in February 2012 that FDA CVM, after completing a scientific review, supported the use of this strain, the Mascoma Grain Technology (MGTTM) yeast product, as a processing aid in the production of animal feed, resulting as a byproduct of the corn ethanol conversion process (presentations made at the time of product launch in June 2012 identified the strain as S. cerevisiae expressing a glucoamylase gene). The February press release further said that CVM sent a letter to AAFCO supporting inclusion of the product as a feed ingredient on the AAFCO Official Publication. Mascoma later announced that the MGTTM yeast product would be jointly marketed with Lallemand Ethanol Technology under the commercial name TransFermTM for use by the fuel ethanol industry, and this product was officially launched at the June 2012 Fuel Ethanol Workshop.

Although this product is not listed on CVM’s online inventory, Mascoma’s 2011 SEC filings from a planned IPO make clear that the company submitted a data package to CVM after obtaining the opinion of an outside expert panel that the MGTTM yeast product qualified for GRAS status. And the February 2012 press release and subsequent marketing documents indicate CVM’s support was achieved. In any event, it appears that Mascoma’s claim is correct that this is “the first bioengineered yeast that has gained the FDA’s acceptance for use in corn ethanol production of distillers co-products for animal feed.”

The path for new applicants to submit notifications to CVM for new GRAS determinations appears straightforward. The data requirements seem to be clear from the regulations and the various pages on the FDA CVM website. As with any regulatory matter, prior consultation with the Agency would be highly advisable, which is particularly true in this instance, where CVM officials would be able to provide specific guidance on how the process works, and how FDA and AAFCO work together. The fact that 10 of the 14 notifications submitted to CVM since the pilot program began in 2010 were not successful may imply that the standards and data requirements of the AAFCO are somewhat high, or it may simply reflect the fact that the notification program is new and may have been unfamiliar to applicants (the success rates for the human GRAS notification program seem much higher). Nevertheless, with proper advance planning, guidance from outside experts, and consultation with the Agency, GRAS status should be achievable for many modified biofuel production organisms intended for use in animal feed.

D. Glass Associates, Inc. is a consulting company specializing in government and regulatory affairs 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.