Impact of 2016 Final Rule on FDA Review of Animal GRAS Notices

Several previous posts on the blog discussed the options for obtaining approval in the U.S. to market new animal food ingredients (such as spent microbial biomass from biofuel or bio-based chemical fermentation runs). One such option was to seek review by the U.S. Food and Drug Administration of a company’s determination that the product is Generally Recognized as Safe (GRAS) for the intended use in animal food. On August 17, 2016, FDA published a Final Rule to formalize the voluntary, interim GRAS notification procedures that had been in effect since 1997 for human food ingredients and since 2010 for animal food ingredients. This post will review the new 2016 policy and discuss how it is being implemented for new animal food substances. [Note that FDA has recently begun using the term “food” to apply both to humans and animals, in lieu of the older term “animal feed”.]

As discussed in more detail in my earlier blog posts in 2013 and 2015, under the Federal Food, Drug and Cosmetic Act, most new substances that are intended to be components of food or to affect components of food are considered to be “food additives” and would ordinarily need to be approved through the submission of a Food Additive Petition.  However, 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 is 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, and other substances were later affirmed by FDA to be GRAS, often in response to manufacturer petitions. In addition, under the law, manufacturers are allowed to self-certify that a product or food additive is GRAS, and many companies have historically taken this route.

Back in April 1997, FDA published a proposed rule outlining a new, voluntary GRAS notification process for both human and animal foods to replace the old petition process, which was becoming unwieldy for FDA to administer. An interim program to review human GRAS notifications using the procedures of the proposed rule was instituted at that time, although a corresponding procedure for animal food ingredients was not instituted until 2010. These programs allowed applicants to submit notifications in which they informed the Agency that they had determined that a food substance qualified for GRAS status. FDA then had 180 days to evaluate whether the notice provided a sufficient basis to support a GRAS determination. The Agency’s determination would be conveyed in an opinion letter to the submitter, which would either state that FDA has “no questions” about the applicant’s determination of GRAS status (a “no action” determination that is the equivalent of approval), or would outline the reasons why the Agency has determined there is not sufficient data to support such a conclusion.

As of mid-2016, the Agency received over 600 Notifications under the interim human GRAS program, the great majority of which received “no questions” letters after FDA review. This program was widely believed to be operating efficiently and to meet industry needs. Unfortunately, the same was not the case for the animal GRAS Notice program, administered by FDA’s Center for Veterinary Medicine, that was instituted in a June 4, 2010 Federal Register notice. The program for animal food is described elsewhere on this blog and on the CVM website, and like the human program, it allowed applicants to submit notifications in which they inform the Agency that they believe an animal food substance qualifies for GRAS status. As I have previously discussed in blog posts in 2013 and 2015, in its first few years, the Animal GRAS Notification program was not particularly successful, and was not being administered by FDA CVM very efficiently.

On August 17, 2016, FDA published a Final Rule to formally institute a final, somewhat revised notification process under which any person may notify FDA of a conclusion that a substance for use in human or animal food is GRAS under the conditions of its intended use. The Federal Register notice announcing this final rule included a lengthy discussion of the comments FDA received in response to the 1997 proposed rule, and discussed the results of the interim notification programs. In adopting the final rule, FDA also issued revised, clarified guidance for the data and other information it expects to see in what are now called “GRAS Notices”. The rule became effective on October 17, 2016, and is now in full effect for both human and animal food ingredients. The text of the relevant portions of the regulation as they apply to the animal GRAS program, 21 CFR Part 570, can be found here.

The procedures for submitting GRAS Notices and FDA’s process for their review are substantially the same as under the interim policy. After making an initial determination of the suitability and completeness of a Notice for a food ingredient (“notified substance”), which in practice may take several months, FDA has 180 days to review the Notice and is obligated to inform the submitter of their findings within that time period. However, the Agency may also extend that period by up to 90 days, by notifying the submitter within the first 180 days.

Most importantly, the final rule standardized the format for GRAS Notices and specified what data and other information is to be included in each of seven required parts of the Notice. The seven parts of the notice are shown in summary form below – the more detailed outline as specified in the regulation can be found in the Federal Register notice. The complete outline goes into considerably more detail about the data and information required in the various sections, particularly Parts 2, 3, 6 and 7. The requirements for the human and animal GRAS programs are slightly different, and the version for the Animal GRAS program is the one shown below.

Required Components of a GRAS Notice for an Animal Food Substance
Part 1.  Signed statements and a certification.
Part 2. The identity, method of manufacture, specifications, and physical or technical effect of the notified substance.
Part 3. Dietary exposure (to the target animal and/or to humans) to the notified substance.
Part 4. Self-limiting levels of use in circumstances where the amount of the notified substance that can be added to human food or animal food is limited because the food containing levels of the notified substance above a particular level would become unpalatable or technologically impractical.
Part 5. The history of consumption of the substance for food use by a significant number of consumers (or animals in the case of animal food) prior to January 1, 1958, if a conclusion of GRAS status is based on common use of the substance in food prior to 1958.
Part 6. A narrative that provides the basis for the notifier’s conclusion of GRAS status, including why the scientific data, information, methods, and principles described in the notice provide a basis for the conclusion that the notified substance is generally recognized, among qualified experts, to be safe under the conditions of its intended use.
Part 7.  A list of the generally available data, information, and methods the notifier cites in the GRAS notice.

At this writing, the new policy has been in place for nearly 18 months, and so it is reasonable to see how FDA CVM is doing administering the Animal GRAS program. As shown on the Animal GRAS Notice Inventory page, there have been 25 notices submitted since the program began, five of which were submitted since the final regulations came into place (it’s not clear how up-to-date the web listing is, and it is possible that there are a number of other submissions that CVM is now reviewing but which are not yet posted on the website – I am aware of at least one). Of these 25 submissions, 4 are listed as “pending”, 9 received the “no questions” letter as the equivalent of approval, 6 were rejected by FDA as “not providing a basis for a GRAS determination”, and another 6 were withdrawn by the applicant (i.e., “at notifier’s request, FDA has ceased to evaluate the notice”). A few trends are evident from this listing:

  • Of the notices for which a decision was made, only a little less than half were favorably reviewed by FDA (9 out of 21).
  • Of the 5 notices submitted since the final rule came into effect, 3 are still pending, one was rejected as not providing a basis for the determination (AGRN 22, from Royal Canin US for a marigold extract); and one successfully received the “no questions” letter (AGRN 21, from Agrivida for ground grain from a genetically modified strain of corn expressing a phytase enzyme).
  • The five most recent “no questions” determinations all required between 9-12 months from the time FDA formally accepted the filing to the date of the opinion letter. The 6th most recent, a submission for a phytase enzyme from DSM, took only 6 months for FDA’s decision in 2012-13. Note that it commonly took a month or more from the actual submission date for FDA to complete its initial review and formally record the notice as being filed, so the actual review time at the agency was a little longer in all cases.
  • There has only been one Notice since 2011 that was rejected by FDA (AGRN 22, discussed above), and it took FDA about a year to make this determination. However, there were several Notices since 2011 that were withdrawn, which suggests that FDA’s preferred way of operating is to give the submitter the option to withdraw rather than to receive a negative decision letter.
  • Of the four Notices still pending, one has been pending since March 2016 (AGRN 19 for L-glutamine to be fed to post-weaning horses) while the others have been filed more recently.

It is too early to know if the final rule and the clarified guidance for the data to include in the submission are having any effect on making the process easier for companies to comply with, or whether the rule has made FDA’s review process more efficient. I can say from my own experience helping clients with FDA and AAFCO submissions (the latter of which are also reviewed by CVM’s technical team) that CVM staff review these submissions at a very high level of detail, and want to see a comprehensive and thorough data set that is free of incomplete or ambiguous descriptions, and which addresses all the issues which CVM believes are relevant to the analysis. CVM staff also requires that an exhaustive literature search be performed and documented, to ensure that there is no prior literature that might contradict the applicant’s determination of the safety of the substance. And having helped one client prepare a GRAS Notice under the new guidelines, I can say that it is an exacting process, and that it can be quite challenging to assemble all the information that FDA wants to see, in the specific format now required under the rule and to the level of detail expected in accordance with CVM practice. On the other hand, because CVM’s technical reviewers give a higher priority preference to GRAS Notices (and food additive petitions) than for AAFCO new ingredient definition requests, the pendulum has shifted and many are coming to feel that the GRAS Notice process is a quicker and more straightforward path for approval of new animal food ingredients, particularly those that are based on microorganisms.

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. 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 any other organization with which Dr. Glass is affiliated.

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MCANs Reviewed by EPA Since 2016 TSCA Reform

Many were curious, as I speculated in an earlier blog post, whether EPA’s procedures for reviewing Microbial Commercial Activity Notices (MCANs) and chemical Premanufacture Notices (PMNs) under the Toxic Substances Control Act (TSCA) would be changed by the landmark TSCA reforms enacted in the June 2016 passage of the Frank R. Lautenberg Chemical Safety for the 21st Century Act. Although the Lautenberg Act had no provisions specifically affecting EPA’s biotechnology program under TSCA, some portions of the bill have caused EPA to change the way it reviews MCANs, the determinations it makes regarding each MCAN, and the way in which it publicizes the results of its review. But would this lead to any appreciable changes in EPA’s biotechnology program?

Specifically, the Lautenberg Act required EPA to affirmatively reach one of the following three determinations for each notice submitted:

  • A finding that the substance presents an unreasonable risk.
  • A finding that either the information is insufficient to permit a reasoned evaluation of the substance; or in the absence of sufficient information and evaluation, the substance may present an unreasonable risk; or the substance may be produced in substantial quantities or may enter the environment in substantial quantities, which may lead to substantial human exposure.
  • A finding that the substance is not likely to present an unreasonable risk.

Although largely conforming to prior practice regarding EPA’s risk assessment procedures, the key difference was that EPA now needs to affirm one of these determinations for each MCAN or PMN it reviews, whereas previously if the Agency took no action within the 90 day review period, the Notice was deemed to be accepted (“Dropped from Review”), and the chemical or the microorganism covered in the Notice could proceed to be commercialized.

EPA began following this procedure for all MCANs filed after the June 22, 2016 signing of the Lautenberg Act. For almost all of these MCANs, EPA was able to reach the finding that the microorganism “is not likely to present an unreasonable risk”, and to adopt the necessary paperwork as now required under the amended TSCA. At this time, the Agency also changed the way it had been reporting the filing and disposition of MCANs, and although the new procedures are in conformance with the requirements of the law, the new publication procedures have made it somewhat harder to track MCANs and to easily obtain information on the organism and its intended use covered in each reviewed MCAN.

EPA previously maintained a page entitled “TSCA Biotechnology Notifications Status” (now accessible here), where it chronologically listed all the MCANs (as well as TSCA Experimental Release Applications and Biotechnology Test Marketing Exemption Applications) reviewed by the Agency since 1998 (i.e. since the adoption of the current MCAN regulations). The tables on this page conveniently listed, for each MCAN, the name of the organism, the name of the submitter, and the intended use (except when any such information was claimed as confidential by the submitter), and more importantly each entry also had a link to a page with a 1-2 paragraph description of the organism and its intended use, and an explanation of the basis for EPA’s finding of no unreasonable risk. These tables can still be found at this site, although the links to the decision documents seem to be gone. But this page was convenient because it listed all biotech notices on a single page, separately from chemical PMNs, and it was easy to find and review the most recently-filed notices. In the past, I’ve posted periodic summaries of recently-filed MCANs, using information drawn from this page.

Since the passage of the Lautenberg Act, however, EPA has begun to use a new page where it publicizes all TSCA Section 5 Notices for which it has made the “no unreasonable risk” determination. This page, called “Chemicals Determined Not Likely to Present an Unreasonable Risk Following Pre-Manufacture Notification Review“, lists both MCANs and PMNs in the chronological order in which the determination has been made (additions to this page are announced from time to time in the Federal Register). From this page, you can follow links to a page entitled “Microbial Commercial Activity Notices (MCANs) Table” which indeed lists only reviewed MCANs, but the”No Unreasonable Risk” page is difficult to review and search because it intermingles PMNs and MCANs (note that PMNs and MCANs can be distinguished because PMNs are identified with a prefix of “P” followed by the fiscal year of submission, while MCANs are identified with a “J” and the fiscal year) The”No Unreasonable Risk” page does include links to EPA’s decision documents for each Notice (for example, this one here), but these documents are highly formulaic to meet the requirements of the law, and include little if any detail about the specific organism in question.

So, it is harder now to conveniently and quickly get an overview of recent MCAN activity, and so I’ve done the hard work for you. The table below shows all MCANs received by EPA since June 22, 2016 for which the Agency’s review has concluded. This table shows the MCAN number, the species of the microorganism, and the dates on which EPA review began, the date of EPA’s decision, and the effective date of the decision (i.e. the end of the review period, usually 90 days after submission). Each entry has a link to EPA’s decision document, although the link will first take you to an intermediate page, from which the actual decision document can be accessed.

Case Number Chemical Identify Final Disposition Review Start Date Decision Date Effective Date
J-16-0006 Generic: Trichoderma reesei modified Not likely to present an unreasonable risk 6/22/16 9/2/16 9/7/16
J-16-0010 Generic: Saccharomyces cerevisiae modified Not likely to present an unreasonable risk 6/22/16 9/14/16 9/15/16
J-16-0011 through 0016 Generic: Biofuel Producing Organism Not likely to present an unreasonable risk 6/22/16 9/14/16 9/15/16
J-16-0017 Generic: Saccharomyces cerevisiae modified Not likely to present an unreasonable risk 6/22/16 9/14/16 9/15/16
J-16-0018 Generic: Saccharomyces cerevisiae modified Not likely to present an unreasonable risk 6/22/16 9/14/16 9/15/16
J-16-0019 Generic: Trichoderma reesei modified Not likely to present an unreasonable risk 6/29/16 10/4/16 10/11/16
J-16-0020 Generic: Trichoderma reesei modified Not likely to present an unreasonable risk 6/29/16 10/4/16 10/11/16
J-16-0021 Generic: Trichoderma reesei modified Not likely to present an unreasonable risk 7/15/16 10/19/16 10/25/16
J-16-0022 Generic: Trichoderma reesei modified Not likely to present an unreasonable risk 7/15/16 10/19/16 10/25/16
J-16-0023 Generic: Trichoderma reesei modified Not likely to present an unreasonable risk 7/16/16 10/19/16 10/25/16
J-16-0024 Generic: Trichoderma reesei modified Not likely to present an unreasonable risk 7/28/16 11/14/16 11/21/16
J-16-0025 Generic: Trichoderma reesei modified Not likely to present an unreasonable risk 7/29/16 11/14/16 11/21/16
J-16-0026 Section 5(e) Consent Order – May present an unreasonable risk of injury to health and the environment 4/10/17
J-16-0033 Generic: Saccharomyces cerevisiae modified to express glucoamylase activity Not likely to present an unreasonable risk 8/22/16 12/1/16 12/7/16
J-16-0034 Generic: Saccharomyces cerevisiae modified Not likely to present an unreasonable risk 8/23/16 12/1/16 12/7/16
J-16-0035 Generic: Saccharomyces cerevisiae modified Not likely to present an unreasonable risk 8/23/16 12/1/16 12/7/16
J-16-0036 through 0041 Generic: Biofuel producing modified microorganism(s), with chromosomally-borne modifications Not likely to present an unreasonable risk 9/7/16 12/1/16 12/7/16
J-17-0001 through 0005 Generic: Saccharomyces cerevisiae modified Not likely to present an unreasonable risk 10/24/16 1/18/17 1/25/17
J-17-0006 Generic: Saccharomyces cerevisiae modified Not likely to present an unreasonable risk 11/23/16 2/13/17 2/13/16
J-17-0007 Generic: Biofuel producing Saccharomyces cerevisiae modified, genetically stable Not likely to present an unreasonable risk 2/1/17 4/27/17 4/27/17
J-17-0008 through 0013 Generic: Modified microorganism Not likely to present an unreasonable risk 5/8/17 7/27/17 7/27/17
J-17-0014 Generic: organic acid producing yeast, modified, genetically stable Not likely to present an unreasonable risk 

 

7/10/17 10/5/17 10/6/17

There is considerably less information now available about filed MCANs on these pages, and all the company names have either been claimed as confidential or simply omitted, but it is clear that the bulk of the activity is for familiar species of microorganisms. Specifically, there are 8 MCANs for modified strains of Trichoderma reesei, all of which are for enzyme production (some specified as “cellulose-degrading” enzymes) and thirteen MCANs for strains of Saccharomyces cerevisiae, all for production of ethanol. All but one of the T. reesei MCANs were filed in the span of a month in the summer of 2016 and thus may have come from the same company. There were a total of 12 MCANs for “generic biofuel producing organisms”, filed as two separate consolidated MCANs in June and September 2016, and one MCAN for an “organic acid producing yeast” of an unnamed species. There was also one MCAN that became the subject of a consent order, although details of this case do not seem to be available online.

There appear to have been as many as 41 MCANs submitted during Fiscal Year 2016 (October 2015 through September 2016), but only about 14 submitted through the first 10 months of Fiscal Year 2017 (i.e. through July 2017), although the full number received during FY17 has not yet been publicized. It would be interesting to see if the overall numbers for FY17 are indeed down from prior years, and whether this might represent a trend from the prior several years where MCAN numbers increased from year to year. This would not necessarily be surprising, in view of the financial difficulties that many in the biofuel sector have experienced in recent years.

It is somewhat surprising, and perhaps ironic, that the new procedures put in place under the Lautenberg Act have caused EPA’s MCAN listings to be less informative than the old practice. Many observers expected the Lautenberg Act to make EPA’s review of chemical substances more transparent than under existing practices, but these new websites are harder to use to extract useful information. Not only is it beneficial for the general public and environmental group watchdogs for EPA’s MCAN review process to accessible to the public, but these listings have also been useful to industry as a source of competitive information. On the other hand, EPA’s old listings page was notoriously slow to be updated, often no more than once a year, so at least the new listings pages seem to be reasonably up to date in listing decisions: at this writing in January 2018, the “No Unreasonable Risk” page lists PMN decisions made as recently as December 2017, although the most recent MCAN determination was from October of last year.

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. 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 any other organization with which Dr. Glass is affiliated.