Proposal to Simplify FDA Review of Microbial Feed Ingredients

I recently submitted comments to the White House Office of Science and Technology Policy on several aspects of industrial biotechnology regulation, as OSTP has continued to spearhead the President’s directive for federal agencies to revisit the Coordinated Framework for Biotechnology Regulation (as discussed in my August 5 post on the blog). This submission expanded on comments I submitted in October to the EPA on specific aspects of the TSCA regulations, and addressed several aspects of the U.S. federal government’s regulation of biotechnology by the EPA, FDA and USDA.

My new comments included some specific proposals relating to FDA’s programs for reviewing proposed uses of modified microbial strains for use as feed additives. Companies developing novel microbial strains for the production of biofuels or bio-based chemicals often plan to use the spent biomass after fermentation as a nutritional additive to animal feed. Having an efficient regulatory process that allows timely product approvals while still ensuring product safety is critical for the success of such company plans. I therefore recommended that FDA critically review and revise its existing procedures for reviewing novel animal feed ingredients based on genetically modified microorganisms. My specific suggestions were to provide a more precise definition of what constitutes a “genetically modified” microorganism, and to establish a separate procedure for FDA review of modified microbial strains where the nonmodified species has GRAS status for the intended use and/or a long history of safe use in human and animal food. I’d like to elaborate on this recommendation in this post, and in the one that will follow.

I’ve described the situation regarding review of animal feed ingredients in earlier blog posts. Under the current system, there are several alternative paths companies might take for approval, all of which appear to apply the most rigorous safety standards even for products similar to those already on the market. I understand and appreciate that animal feed ingredients must be shown not only to be safe and effective for the target animal, but in the case of food-producing animals that the ingredient is also safe for human consumption, and that reviews of microbial feed ingredients must be consistent with longstanding regulations and practices of FDA’s Center for Veterinary Medicine (CVM) and the Association of American Feed Control Officials (AAFCO). However, these procedures, as applied to proposed ingredients that are modified versions of common microbial species with long histories of safe use in food and feed, can be time-consuming and onerous in ways that are not commensurate with the potential risks of this class of product. This is particularly true for modified strains of Saccharomyces cerevisiae intended for use in dried distillers grains or other distillers’ co-products. Even though, in this scenario, the modified microorganism would make up only a very minor component of the finished animal feed, companies seeking such approvals face a conflicting array of possible alternative strategies, all of which entail lengthy review times that are inconsistent with the low potential risks of such products. The difficulties some yeast strain developers have faced have been well documented, including in a recent article in Ethanol Producer Magazine.

This problem is exacerbated by the fact that FDA does not have a consistent, clear definition of what is “genetically modified”, that might clarify to what extent genetic modifications change the regulatory status of an existing product. This uncertainty can be traced back to FDA’s statement of policy in the Coordinated Framework, where the Agency said:

Comments [received from the public in response to the earlier-published 1984 policy statement] 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 and the provisions of section 409 would apply. (emphasis added)

In practice, this has led to confusion in certain sectors of the industry on the question of whether minor, often intra-specific, modifications or single-gene insertions to a common food microorganism result in a “modified organism” that requires regulatory scrutiny. Although I have heard, anecdotally, that there are modified yeast strains on the market, self-certified as GRAS by the manufacturer, I know that often, companies are not clear to what extent relatively minor genetic manipulations result in the need for de novo regulatory review. Furthermore, small companies may be reluctant to introduce modified strains without having review or approval from a regulatory body, and the purchasers of such strains may similarly be reluctant to use them in DDGs without regulatory review from either FDA or AAFCO.

In my comments, I recommended that FDA review its definitions and procedures, paying specific attention to whether a class of products can be defined where the potential risks are low enough so that expedited procedures could be adopted. This could encompass one or both of the following options:

  • Provide a definition of “genetic modification” that specifies a class of modifications that can be assumed a priori to have not altered the status of an otherwise-GRAS microorganism, so that minimal or no agency review would be needed for the developer of the stain to certify GRAS status. For example, this might include strains modified only by gene deletion or directed evolution.
  • Adopt a streamlined review process for those genetically modified microorganisms where the host organism has a long history of safe use in animal or human food, with S. cerevisiae commonly used in distillers’ co-products to be one prominent example.

The goals of the second bullet point might be accomplished in several ways, including:

  • Utilize the current CVM GRAS Notification program, but provide an alternative, streamlined path and shortened review time for modifications to microorganisms with long histories of safe use in food, or
  • Adapt FDA’s existing program for consultations on genetically modified food plants so that its scope can include microorganisms with long histories of safe use in food, or create a parallel program for such modified microorganisms.

The first suggestion may be a viable option, although many have observed that CVM’s GRAS Notification program has not yet been proven to be a useful route for industry. Under this program, FDA has received only 18 submissions since 2010, of which only 7 received favorable “FDA has no questions” determinations. Importantly, CVM has not yet concurred with a single GRAS Notification for animal feed use of modified S. cerevisiae strains, having rejected or caused the withdrawal of all three submitted to date. FDA has also rejected as “not providing a basis for a GRAS determination” a notification for animal feed use of Bacillus cereus variant toyoi.  In contrast, FDA’s review procedure for the GRAS status of human food ingredients has been more effective: as of this writing, FDA has received almost 600 GRAS Notifications for human food substances since 1997, the great majority of which have been successfully reviewed and cleared within 9-12 months or less. Nevertheless, if CVM reviews of GRAS notices for the most common microorganisms can proceed along a separate, streamlined path, this may be a possible option.

I believe the second suggestion is a promising approach that is worthy of FDA’s serious consideration. This program of consultation on genetically modified foods was put into place in 1996 (modified in 1997) as FDA began receiving requests from companies that had made their own determinations that their transgenic (i.e., “GMO”) plant varieties could be safely used in foods but wanted to be able to inform FDA about their plans to begin marketing such varieties. As described in the website linked above, this program features guidance for companies as to the specific information to be provided for FDA review under this voluntary consultation program, and specifies the procedures FDA will follow to review such requests. The program appears to be working well, with, at this writing, 168 consultations having been successfully reviewed by the agency, although it’s worth noting that many public interest groups who oppose the presence of GMOs in food have been critical of this program and have questioned whether it allows adequate scientific reviews.

To date, the GM food consultation program has been limited to modified plants: in fact, under this program, the term “genetic modification” is defined to mean “the alteration of the genotype of a plant using any technique, new or traditional” (emphasis added). This program has not been applied to genetically modified microorganisms, but I think it offers a useful model for FDA to consider in adopting a process to expedite reviews of products such as modified yeasts for production of distillers grains, or other products encompassing well-defined modifications to microorganisms commonly used in food or feed. I plan to expand upon this recommendation and provide further details in a subsequent blog post, and I welcome feedback and comments on this suggestion.

Although I am fully aware of the need for adequate safety assessments of proposed animal feed ingredients, currently-practiced procedures are placing an inordinate burden on companies in the industrial biotechnology sector that are seeking to solve important global problems with novel microbial technologies. The length and complexity of these regulatory reviews far exceed the minimal risk posed by those products consisting of well-characterized modifications to familiar microorganisms with long histories of safe food use. This has created regulatory barriers which are inhibiting the ability of companies to bring these technologies to market because they cannot take advantage of the added economic value that would come from the use of inactivated microbial biomass 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. 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/djglass99and 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. Please visit our other blog, Biofuel Policy Watch.

My Comments to EPA on Genetically Modified Algae Regulation

In the previous post, I reported on a public meeting entitled “Considerations for Risk Assessment of Genetically Engineered Algae”, that was convened by the EPA on September 30, 2015. EPA solicited further public comment on these issues, in a comment period that ran until October 31. I had given brief oral comments at the public meeting, primarily on behalf of Joule Unlimited Technologies, and then I followed this up by submitting written comments on behalf of both D. Glass Associates and Joule. My oral and written comments addressed specific questions EPA posted prior to the meeting, as well as a draft of a guidance document for industry entitled “Considerations for Risk Assessment of Genetically Engineered Algae” that was posted online ahead of the meeting. The following is a summary of those comments.

My comments began with a general statement of support for reasonable, science-based regulation overseeing the development of industrial biotechnology and ensuring that appropriate risk assessments are made as the technology develops. I’ve always found EPA’s regulatory program to be effective in assessing potential health and environmental risks while offering a clear path for commercial development of those technologies determined not to pose unreasonable risks. I emphasized that industrial biotechnology companies were developing products that hold the promise of substantial societal benefits in reducing greenhouse gas emissions, providing innovative solutions for carbon capture and utilization, and providing environmentally-friendly alternatives to uses of fossil fuels, while avoiding the use of feedstocks based on food crops and without using arable land that would best be used for food production.

Moving next to more substantive comments, I argued that it is important to build a database of environmental effects of algae and cyanobacteria strains that are intended for industrial uses subject to TSCA, but noted that regulatory risk assessments are strain-specific, so a general database of adverse environmental effects, while useful, but would be of little value in a risk assessment of an organism based on a recipient strain with no history of any deleterious traits. I suggested that EPA might compile, or sponsor the compilation of, a database of algal and cyanobacterial strains known in the literature not to express toxins, cause harmful blooms, or otherwise have deleterious effects, so that applicants could be encouraged to select such strains as recipient strains for genetic modification. In any event, however, EPA’s risk assessment of modified algae should focus on whether the introduced genetic modifications change the predicted behavior or risk characteristics of the starting recipient strain, and if such changes are not likely, then the use of the modified strain is unlikely to pose any environmental or safety risks.

The comments went on to suggest that EPA continue to allow MCAN or TERA applicants to rely on genomic or proteomic analysis of proposed recipient strains to address whether such strains produce toxins or might be pathogenic or virulent. This strategy has been pursued at least by both Joule and Algenol in MCANs for cyanobacteria strains, and has been based on the significant literature that has developed on the genes encoding toxin production or other pathogenic traits in algae and cyanobacteria. The ability to quickly and routinely search a sequenced genome for the presence of nucleic acid sequences encoding such function can be a powerful tool in assessing the risks of using such any given recipient strain in an industrial process.

I next pointed out the importance of clarifying that MCANs for contained manufacturing would be evaluated and regulated in a manner different from TERAs or MCANs for open-pond uses. EPA’s guidance and the draft “Considerations” document does specify in several locations which provisions are applicable to open ponds as opposed to contained uses, but EPA should be sure that such guidance is appropriately given throughout the document, for example, clarifying that information on “Monitoring” should primarily be applicable only to proposed open pond uses, and would be applicable to contained uses only in extraordinary situations.

EPA had asked the question of whether there were features of contained photobioreactors that posed potential hazards. I pointed out that it is not the reactor itself that should be considered potentially “hazardous”, because it is the characteristics of the strain that would dictate potential environmental risks. The more proper question to ask is “What information about a containment system should be provided to assess the potential for release of modified algae from the system?” In other words, EPA’s goal should be to develop guidance to help applicants identify and provide information EPA needs to assess the integrity of the reactor, and in fact EPA intends that such guidance would be included as a significant component of the “Considerations” document. Section VI of the draft “Considerations” document, particularly Section VI.B for photobioreactors, seems to be a comprehensive and mostly appropriate listing of such requested data, in that it focuses on information unique to photobioreactors, the materials from which they are constructed, and the manner in which they are used to grow, harvest and handle the modified algae or cyanobacteria.

In both the DGA and Joule comments, I stressed the strong opinion that existing biotechnology laws and regulations around the world are generally sufficient to apply to the potential applications of “synthetic biology” that are contemplated in the near future, and that data requirements under such regulations, including EPA’s TSCA biotechnology regulations, do not need to be substantially changed in order to provide effective oversight over synthetic biology. I cited the findings of several governmental or international bodies that have all come to the conclusion that, at least for the foreseeable future, existing laws and regulations around the world are sufficient to provide for adequate risk assessment and risk management of proposed commercial uses of synthetic biology, and I provided copies of my slides from my July 2015 presentation at the BIO World Congress addressing this very point.

Finally, in my comments on behalf of DGA, I addressed an issue about which some ambiguous comments were made at the September 30 public meeting. That pertains to some confusing terminology in the Part 725 regulations regarding whether the “Contained Structure” exemption for R&D activities applies to commercial entities, and whether the definition in the regulations of “Commercial R&D” applies to companies in a way that might render the exemption unavailable. In my consulting practice I’ve encountered confusion over these issues, and so in my comments I asked EPA to clarify the widespread view within industry that the “Contained Structure” exemption does indeed apply to companies as well as non-profit researchers, provided the appropriate conditions are met.

Please contact me if you would like a complete copy of the DGA comments, which include the Joule written comments in their entirety.

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/djglass99and at www.dglassassociates.com. The views expressed in this blog are those of Dr. Glass and D. Glass Associates and, except as indicated above, do not represent the views of any other organization with which Dr. Glass is affiliated. Please visit our other blog, Biofuel Policy Watch.