Observations from AAFCO Midyear Meeting

I attended the January 2016 Midyear Meeting of the Association of American Feed Control Officials (AAFCO) in Charleston, SC January 17-20, 2016. In addition to its usual format of a general membership meeting followed by a series of committee meetings, this year’s meeting included a special Workshop on the Ingredient Definition Process, which provided a great deal of useful information about the process for the review and approval of new feed ingredients and how companies should prepare the needed dossiers. Links to the agenda for the general meeting and the Ingredient Workshop can be found at http://www.aafco.org/Meetings/Midyear/2016. The following is a summary of some of the key points and insights I learned at the meeting, particularly including the Workshop.

AAFCO carries out most of its functions through its several committees, which each meet during the Annual Meeting in the summer and the Midyear Meeting in January, as well as other times during the year as needed. AAFCO’s work is carried out by a dedicated group of state (and Canadian provincial) government officials, who participate in AAFCO activities as volunteers. AAFCO’s leadership works closely with officials in FDA’s Center for Veterinary Medicine (CVM), several of whom are also active participants in AAFCO’s activities. Overall, I found that the group exhibits a serious dedication to AAFCO’s goals and a high level of attention to detail, which is evidenced by the way they carefully carry out the review and approval of new ingredients and other committee business.

Much of the discussion at the Ingredients Workshop had to do with the data that would be required to support a regulatory assessment of a proposed new feed ingredient. There are three major routes to new ingredient approval, as I’ve explained in previous blog posts: showing an ingredient is Generally Recognized as Safe (GRAS), either through self-certification or review by FDA under its GRAS Notification program, achieving FDA approval as a Feed Additive, or obtaining a new ingredient definition from AAFCO. The review processes and data requirements for these routes are already very similar, and several speakers at the Workshop noted a continuing trend towards further harmonization of the data requirements across all three processes. The three major areas of data required under al these regulatory routes are utility (effectiveness); chemical and manufacturing control information; and safety (animal, human and environmental).

Regardless of which regulatory path an applicant chooses, the technical review would be conducted by the same small group at FDA CVM, which currently has a large backlog. Generally, Feed Additive Petitions have the highest priority, followed by GRAS Notifications and only then by AAFCO requests, so this often results in long review times for many AAFCO ingredient requests. Companies were advised to plan that the AAFCO new ingredient approval processes might last up to 24-36 months.

It is clear from the attention to detail that was shown by committee members towards the various proposals being considered that any application for a new animal feed ingredient will undergo rigorous review for safety, quality and efficacy, not only by the technical reviewers within FDA CVM, but also by the members of the Ingredient Definition Committee who will ultimately vote on any proposed new definition. The discussions showed a high level of attention to detail: for example, the Ingredient Definition Committee seemed reluctant to approve any new definition unless there was a true consensus about the definition and all its details. Several of the committees opted to table certain pending matters until a future committee meeting, to allow unresolved issues to be worked out, or to allow further discussion among stakeholders. In view of the infrequent schedule of committee meetings, such decisions would result in significant delays in adopting new definitions, but members clearly are driven by the need to get things right, rather than any sense of urgency in reaching decisions.

The level of cooperation and collaboration with FDA CVM was not surprising. However, what was somewhat unexpected was the level of industry participation. AAFCO meetings are open to the public, and at the January meeting, industry participants seemed to make up perhaps 30-40% of the overall attendance (if not more), and several industry representatives served as members or advisors to the committees. Industry was represented not only by individual company representatives but also by trade associations, such as the Enzyme Technical Association and trade groups representing meat processors, pet food manufacturers, and others. Several of these individuals and trade groups have had long associations with AAFCO and appeared to play significant roles in certain issues, and to carry a great deal of influence within AAFCO discussions.

Committee discussions of specific issues were all open for general comment from those in attendance and anyone participating online via webinar, and industry representatives often spoke for or against proposals relevant to their business interests. This raises the question of whether the fuel ethanol industry, the industrial biotechnology industry, or individual companies developing potential new microbial feed additives should strive to have greater representation at AAFCO, either working through an established group like ETA, the Industrial Section of BIO or the Distillers Grains Technology Council, or through individual company efforts.

The following are a few more specific regulatory issues that were discussed during the meeting.

  • As a result of a settlement to a 2014 lawsuit filed by the Center for Food Safety, FDA is under a court order to issue a final rule implementing its GRAS Notification (GRASN) program by August 31, 2016. The CFS lawsuit was largely directed at the human GRAS program, but from FDA comments at the meeting, it appears that the rule would finalize both the human and animal GRASN processes.
  • FDA apparently also intends to issue a proposed rule that would have CVM recognize all approved AAFCO definitions as either feed additives or GRAS substances. In addition, AAFCO’s Ingredient Definition Committee is considering a proposal under which substances receiving “no questions” letters from CVM under the GRASN process would automatically become listed in AAFCO’s Official Publication. The proposal was not approved at the Committee’s meeting at the Midyear Meeting, but was tabled so that the opinions of state governments could be solicited.
  • FDA has issued a final version of Guidance document GFI #221, “Recommendations for Preparation and Submission of Animal Food Additive Petitions” (dated June 2015), which had previously been available only in draft. It was stated in the Ingredients Workshop that these data requirements would be fairly consistent across the three possible avenues of review for new ingredients.
  • Although in general, AAFCO and CVM need to review a great deal of data regarding the manufacturing process to assess the quality and purity of the product, for biological products the level of detail seems to be similar to what would be required in a Microbial Commercial Activity Notice (MCAN) that might be submitted to EPA if the product or its production microorganism were a genetically modified microorganism subject to EPA biotechnology regulations.
  • AAFCO and CVM will wish to see data addressing safety in target animal species, carried out in the target animal at the appropriate life stage, in accordance with Good Laboratory practice to the extent possible. Human safety should also be assessed, for products to be fed to food-producing animals. It is possible to address safety concerns via a “white paper” literature survey, although it is likely that this would be applicable only in certain situations and for certain product types.
  • Decisions made by FDA require consideration of environmental impacts, under FDA’s obligations under the National Environmental Policy Act. It is not clear to what extent this applies to AAFCO actions and decisions, since AAFCO is not a federal agency, but this topic was discussed during the Ingredient Workshop.
  • As with any regulatory process, companies are advised to consult at an early opportunity with the applicable AAFCO Investigator (the AAFCO volunteer assigned as the contact person for the relevant ingredient type; listed at http://www.aafco.org/Regulatory), to ensure that the proposed ingredient is given a proper definition and to be sure the appropriate data package is assembled.

Please contact me if you would like more information about any of the topics discussed at the January AAFCO meeting.

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.

Proposed FDA Consultation Program for Modified Microorganisms in Animal Feed

The previous post described comments I recently submitted to the White House Office of Science and Technology Policy on several aspects of industrial biotechnology regulation, including recommendations I made relating to FDA’s programs for reviewing proposed uses of modified microbial strains for use as feed additives. I recommended that FDA critically review and revise its existing procedures for reviewing novel animal feed ingredients based on genetically modified microorganisms, and that the agency consider establishing 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, with S. cerevisiae  used in distillers’ co-products to be one prominent example. I suggested two possible approaches for developing such a streamlined review process: either to use the current CVM GRAS Notification program, but provide an alternative path with shortened review time for modifications to microorganisms with long histories of safe use in food, or to utilize 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. I’d like to expand on the latter proposal, which I see as a more promising approach for timely reviews of such proposals, in a way that is compatible with achieving either FDA-reviewed GRAS status or an AAFCO Ingredient Definition.

I’ve described the situation regarding review of animal feed ingredients in earlier blog posts, and the previous post explained that the several available alternative paths for review of new ingredients by either FDA’s Center for Veterinary Medicine (CVM) or the Association of American Feed Control Officials (AAFCO) appear to apply the most rigorous safety standards even for products similar to those already on the market. These procedures are not commensurate with the potential risks of microbial strains that are modified versions of common species with long histories of safe use in food and feed.

FDA’s 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. The 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 (critiques of this program are quite easy to find on the Internet).

FDA’s website summarizes the program as follows:

The goal of the FDA’s evaluation of information on new plant varieties provided by developers during the consultation process is to ensure that human food and animal feed safety issues or other regulatory issues (e.g. labeling) are resolved prior to commercial distribution. During the consultation process, the FDA does not conduct a comprehensive scientific review of data generated by the developer. Instead, the FDA considers, based on agency scientists’ evaluation of the available information, whether any unresolved issues exist regarding the food derived from the new plant variety that would necessitate legal action by the agency if the product were introduced into commerce. Examples of unresolved issues may include, but are not limited to, significantly increased levels of plant toxicants or anti-nutrients, reduction of important nutrients, new allergens, or the presence in the food of an unapproved food additive. The FDA considers a consultation to be completed when all safety and regulatory issues are resolved.

FDA encourages developers of novel plant species to consult with the agency at an early stage. After any such “Initial Consultations” that may take place, the process includes the following phases of the “Final Consultations” stage of the process.

  • Submission of a summary of the safety and nutritional assessment prepared by the company.
  • Review of the submission by a “Biotechnology Evaluation Team” (BET) comprised of members from FDA’s Center for Food Safety and Nutrition (CFSAN) and the Center for Veterinary Medicine (CVM).
  • If necessary, a meeting between the company and the FDA review team to discuss the data submitted in the summary.
  • FDA request for submission of additional information, if judged necessary.
  • FDA decision on the final data package, conveyed to the submitter in writing, concluding either that (1) FDA has no further questions and considers the consultation closed, (2) FDA concludes that the bioengineered food requires review and approval of a food additive petition, or (3) there are other regulatory issues such as labeling requirements that need to be addressed.

The website includes detailed procedures for how the Initial Consultations and Final Consultations are to take place. Notably, the applicant’s summary document is to be circulated to all members of the BET within 10 days of its receipt, and the BET is to inform the submitter within 4 weeks of the submission whether additional information is needed. There does not appear to be specified time limits for the BET to request a meeting with the submitter, or for the BET to make its final determination and inform the submitter in writing.

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 with only minor modifications, it could well be adapted to allow 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.

The FDA website lists the data that it expects to see in voluntary submissions by industry. This list, as shown in the first column in the Table below, is geared towards submissions of modified crop plants; but it could be modified to accommodate reviews of modified microorganisms as shown in the second column.

  FDA GMO Consultation Proposed New Procedure for Modified Microorganisms
1. 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.
2. 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.
3. Information concerning the sources, identities, and functions of introduced genetic material. Information concerning the sources, identities, and functions of introduced genetic material.
4. 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.
5. 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.
5A. General description of the manufacturing process of the modified feed ingredients.
6. 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.
7. 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.
8. 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.
9. 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.
10A. Other information needed for AAFCO purposes, including: proposed Feed Ingredient Definition and proposed label, etc.

10B. Other information needed for GRAS purposes, including proposed GRAS claim, basis for concluding GRAS status, etc.

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

Items #1 through #5 in FDA’s list include information that most companies would routinely have available or could easily obtain. In fact this information is fairly standard for microbial risk assessments, and would typically be compiled if the microorganism required MCAN reporting to EPA, or for regulatory submissions under any of the current options for FDA or AAFCO review. So these items require little revision to accommodate submissions for microorganisms. FDA’s items #6 through #8 specifically address the need to compare the proposed new food crop to the wild type or other naturally occurring crop of the relevant species, and these too can be modified for use with microorganisms. In fact, item #7 specifically addresses the issue that I feel is the key to the use of this process for common microorganisms – in my proposal, this question would ask whether the genetic modification caused any change of composition or properties that would be expected to negatively affect the safety or nutritive value of the feed ingredient prepared using the modified microorganism, and would generally require the applicant to perform such a comparison at the level of the ultimate feed ingredient (e.g. to prepare dried distillers grains from both a wild-type and modified S. cerevisiae strain and to compare their composition and nutritional content).

Finally, the list of requested data could be adapted to add information that might be required if the applicant were to request a new feed ingredient definition from AAFCO, or to include information needed for FDA review of a GRAS notification. The chart shows one possible way this could be done. This would present the clear advantage that any dossier deemed complete under the proposed new process would a priori be sufficient to be used to support an AAFCO request or a GRAS notification to FDA, thus allowing this new process to be consistent and compliant with existing FDA and AAFCO procedures.

Other aspects of a consultation program for microorganisms can be implemented using the procedures described above for the GMO plant consultation program, although one suggestion would be to increase the participation of CVM scientists in the Biotechnology Evaluation Team (for the current program, CFSAN staff make up the majority of these teams). I don’t know whether a program such as this would overly burden existing CVM staff, and this would have to be considered in adopting such a program.

Instituting this new procedure could provide industry with a new route to establish either FDA-reviewed GRAS status, or the basis for an AAFCO Ingredient Definition with reasonable data requirements commensurate with the expected low risks, and a predictable timeline. But of course the key question is whether such a new procedure would lead to a substantial improvement in review times for this class of microbial feed ingredient. A 2006 publication in Nature Biotechnology reported that the average review time (from original submission to FDA decision letter) for the 67 voluntary biotechnology food submissions reviewed by FDA between 1994 and 2005 was 8.55 months, although reviews from 2001-2005 averaged review times of 15.2 months. There does not appear to have been any published studies analyzing review times since 2005, but I have performed a similar analysis for the more recent submissions listed on the inventory website (2007 through 2015, as there were no approvals issued in 2006). The trend towards longer review times has indeed continued: the overall average time from original submission to FDA letter for these more recent submissions was 20.0 months, with the average for certain years (2009, 2012 and 2015) at or close to 24 months. In all but one of these cases, the applicant had to submit additional data requested by FDA, often in multiple instances, and company response times significantly contributed to the lengths of the reviews (on average for 2007-15, FDA was able to issue its decision letter within 6 months of the applicant’s final submission completing the submission of all the requested data).

If this program were to be adapted for use with microorganisms, I expect that there would far less variation in technical content among the submitted applications, and that the required data set would be more consistent and predictable, so that FDA’s reviews should go more quickly than they have for GMO plants, and there should be less of a need for FDA to ask for more data. If it were possible for review times under the proposed new program to be perhaps 9-12 months, that would be better than the existing status quo. It has been reported in public presentations by Mascoma that achieving full approval of a new AAFCO ingredient definition for a modified yeast can take up to 3 years, and approvals under CVM’s GRAS Notification process have been more problematic, in that to date no notifications for modified microorganisms have been cleared by the agency.

Adopting the proposed new process would provide at least one other advantage over the current system, in that it would establish timelines and expectations for FDA review of submitted dossiers, and it would provide a mechanism for an ongoing dialogue between agency reviewers and submitters, something which has been alleged to be lacking under the CVM GRAS Notification procedure (as reported in the article in Ethanol Producer Magazine article, CVM has simply been issuing negative rejection letters rather than entering into dialogue with submitters about needed data) . Additionally, I expect that there would only be a handful of applications in the first year or two in which such a program would be implemented, which would give industry and the FDA the time to work the bugs out of the system, so that it would ultimately operate quite smoothly.

I will be soliciting input and comments on this proposal in the weeks to come. Please feel free to submit a Comment on this blog post, or to contact me offline with any comments, suggestions, etc.

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.

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.

Summary of EPA Public Meeting on Algae Risk Assessment

In a previous blog post, I reported that EPA announced that it was initiating a project to examine and promote “public dialog” about the development and use of genetically modified algae and cyanobacteria, including organisms modified by synthetic biology, intended for industrial purposes including those subject to the Agency’s TSCA biotechnology regulations. In my most recent post, I conveyed the news that EPA had scheduled a public meeting to solicit comment on these topics. This meeting was held in Washington, DC on September 30, 2015, and the following is a summary of the meeting.

The public meeting was entitled “Considerations for Risk Assessment of Genetically Engineered Algae”. The home page for this workshop can be found here, and it has links to the three EPA PowerPoint presentations made at the workshop as well as the background papers issued prior to the meeting. As stated on the website, the objective for the meeting was to “receive public input and comments on EPA’s data needs to support risk assessments of biotechnology products subject to oversight under the Toxic Substances Control Act (TSCA) that make use of genetically engineered algae and cyanobacteria”. Shortly before the meeting, the agency posted on the website two draft documents outlining data requirements for TSCA submissions featuring algae or cyanobacteria or those involving “advanced genetic engineering techniques”. These will be used to update the 1997 “Points to Consider” document, and public comment on these drafts was requested.

The meeting was well attended, with approximately 100 people registered to attend either in person or via webinar. The format of the meeting is shown in the Workshop agenda. After an introductory presentation by Jeffrey Morris, Deputy Director for Programs at OPPT, there were three substantive presentations, each followed by a period for comments by attendees. These sessions were as follows:

Presentation #1. Toxic Substances Control Act Oversight of New Organisms. Dr. Mark Segal of EPA OPPT made this presentation, giving an overview of EPA’s program of regulating biotechnology under TSCA, using its authority to regulate the entry into commerce of new chemicals not regulated by the federal government as foods, drugs, cosmetics or pesticides.

Presentation #2. Considerations for Risk Assessment of Genetically Engineered Algae. Dr. Gwen McClung of EPA OPPT made this presentation, focused on criteria that may make algae different than other microorganisms in the context of the TSCA regulations, which were formulated in the 1990s with traditional industrial microorganisms in mind.

Presentation #3. Considerations for Risk Assessment of Genetically Engineered Microorganisms.  This presentation was made by Dr. Carolina Peñalva-Arana, of the Risk Assessment Division of OPPT. This presentation focused on the more recently-developed techniques of biotechnology, including synthetic nucleic acid technologies, and the need for EPA’s data requirements under TSCA to take such methods into account.

There was also a final session on “Comments/Discussion on Relevant Topics not Covered Previously.”

EPA will continue to take public comments until October 31, 2015. The agency’s overall goal is to provide updated guidance for regulated parties regarding the types of data and information it wishes to see in reviewing Microbial Commercial Activity Notices (MCANs) and TSCA Experimental Release Applications (TERAs) for modified algae and cyanobacteria.

The following are my overall impressions and analysis of the public meeting and the discussions and comments from participants.

  • In my view, EPA appropriately laid out the need to reassess its data requirements for potential uses of algae and cyanobacteria, which were not contemplated when the regulations and the Points to Consider document were finalized in 1997. EPA did this without asserting that such uses carried any greater risk than other microbial technologies. However, I felt that the agency’s case for the need for new data requirements for “synthetic biology” was not as compelling, other than to acknowledge that techniques now exist that were not contemplated in the 1990s.
  • Comments from regulated companies and at least one law firm active in the field were largely supportive of EPA’s role in regulating algae and cyanobacteria, and several of the presentations made specific policy suggestions or pointed out areas for which the agency should devote attention in further developing its regulatory policies towards algae and in developing the technical information needed in support of such policies.
  • Several public interest groups or academic researchers expressed concerns over the possible risks or environmental impacts of the industrial uses of genetically modified algae, including algae modified using synthetic biology. The academic comments were mostly directed at the need for appropriate studies and whether the existing literature was adequate. The public interest groups who spoke were mostly ones that are opposed to, or concerned about, biotechnology in general, and so their concerns over genetically modified algae were not surprising, and if anything there were fewer representatives of such groups at the meeting than one might have expected. However, for the most part, their concerns had to do with the adequacy of the regulations to cover synthetic biology, as well as more general perceived shortcomings of the TSCA regulations (e.g. lack of outside review of MCANs, prevalence of confidentiality claims, whether the burden of proof should be on the submitter rather than the agency). Aside from one group calling for a moratorium on uses of industrial algae, I don’t recall hearing any substantive comments explicitly raising concerns about uses of algae or cyanobacteria per se.
  • There was some discussion on how the TSCA biotechnology program would be affected by the recent White House directive for EPA, FDA and USDA to revisit their biotechnology programs under the Coordinated Framework or by ongoing Congressional efforts to revise and reform the basic TSCA legislation, but EPA had little to say about either situation.

I presented some brief oral comments at the meeting, on behalf of one of the companies for whom I consult. The company will be submitting written comments before October 31, and I will likely submit some additional comments in m own name. I’ll update the blog as new developments warrant.

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.

EPA Public Meeting on Considerations for Risk Assessment of Genetically Engineered Algae

In the previous blog post, I reported that EPA announced that it was initiating a project to examine and promote “public dialog” about the development and use of genetically modified algae and cyanobacteria, including organisms modified by synthetic biology, intended for industrial purposes including those subject to the Agency’s TSCA biotechnology regulations. The Agency’s plans have become more clear, and the public meeting mentioned in EPA’s late July announcement has now been scheduled for Washington, DC on September 30, 2015.

Shortly after the initial announcement, EPA reposted a revised project description on its website, clarifying that the project would primarily be focused on developing data to allow assessment and monitoring of uses of modified algae and cyanobacteria. The modified description can be found here on the EPA website. Further information was then made available when the Agency received approval to announce its plans in the Federal Register, in an announcement that appeared on August 25, which formally announced that a public meeting entitled “Workshop for Public Input on Considerations for Risk Assessment of Genetically Engineered Algae” would be held in Washington on September 30, 2015. At the same time, the Agency created a docket page on the government’s regulations.gov website, and EPA posted the agenda and the “Charge Questions” for the September 30 public meeting for accessing and downloading on this docket page.

As it turns out, the discussion questions in fact touch on synthetic biology (“advanced genetic engineering”) as well as algae biology (“algae mass production”). The questions have been grouped into two categories (along with a third, inviting questions on topics not covered in the stated questions). The six substantive Charge Questions can be summarized as follows (the specific, more detailed questions can be found in the posted documents):

Algae Mass Production: Intrinsic Hazards and Effects Data.

  1. What hazards may be associated with the mass production of algae, other than toxins and harmful algal blooms?
  2. What data are available to allow risk assessment of proposals for algal mass production?

Algae Mass Production: Exposure

  1. What potential hazards are posed by the different containment systems (e.g. photobioreactors) being considered for industrial use of algae, and how should such hazards be evaluated?

Advanced Genetic Engineering

  1. What information should be included in EPA submissions on the construct used to develop a new organism which has been altered using synthetic biology techniques?
  2. How can the predicted function of a genetically engineered construct be shown to be limited to the purpose for which it was designed (e.g. for genes known to encode multiple functions)?
  3. In submissions involving synthetic xenonucleic acid-based constructs, what biological containment methods are best employed?

I will be attending EPA’s public meeting next month, and between now and then I’ll be developing some detailed comments in response to these questions in conjunction with one or more of the companies for whom I consult. I plan to post such comments and other observations about these questions on the blog, and I will also report on the EPA meeting after it takes place. In the meantime, I’d be happy to answer any questions anyone may have about this process, EPA’s intentions, and how it fits into the “big picture” of EPA’s biotechnology regulatory program.

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.

Recent Developments in U.S. Biotechnology Regulation

There have been two recent developments in U.S. federal government biotechnology regulation that may affect industrial biotechnology activities. I’m writing with some brief comments about these two recent announcements, to be followed in the days to come by more comprehensive analysis and discussion.

EPA Biotechnology Regulation

Of most significance to companies developing fuels, chemicals or enzymes using modified microorganisms, last week EPA quietly posted on their website a document entitled “US Environmental Protection Agency GM/Synbio Algae Project”. In this document (dated June 15 but apparently not posted until July 30), EPA announced that it was initiating a project to examine and promote “public dialog” about the development and use of genetically modified algae and cyanobacteria, including organisms modified by synthetic biology, intended for industrial purposes including those subject to EPA’s TSCA biotechnology regulations. The centerpiece of this process will be an updating of EPA’s 1997 “Points to Consider” guidance document for companies submitting notices under the TSCA regulations, to reflect new technologies that are not reflected in the guidance document. The document describes the project as follows:

EPA is currently updating the Points to Consider to accommodate the development of new information relevant to risk assessment of biotechnology products regulated under TSCA. This document currently identifies a broad range of risk assessment topics relevant to TSCA biotechnology submissions, providing technical support to assist those who must prepare microorganism premanufacturing notifications to EPA under TSCA. Those Points to Consider do not currently provide specific support for those using the emerging technologies of algae production and synthetic biology. To keep its risk assessment process for GM/synbio algae open and transparent, EPA intends to develop a separate document on the scientific and technological issues it currently understands to be key and unique for evaluating risks from the production and use of GM/synbio algae. EPA will develop its “Considerations for GM/Synbio Algae” document in parallel with updating the Points to Consider document.

So, in addition to merely updating the Points to Consider document to account for new technology developments, the agency intends to create a new guidance document specific for submissions involving algae or cyanobacteria, as well as for organisms created using synthetic biology technologies. As part of this process, EPA is hoping to convene a public meeting during the week of September 28, 2015, possibly co-located with the Algae Biomass Summit taking place that week in Washington, DC.

It happens that I’ve just recently given two presentations at the 2015 BIO World Congress on Industrial Biotechnology, that touch on both issues raised by EPA’s action — regulation of synthetic biology and regulation of modified algae. In these talks, I make the arguments that existing biotechnology regulations and risk assessment methods are sufficient to regulate industrial uses of synthetic biology,and that a roadmap exists under current EPA regulations for companies to obtain straightforward approvals of uses of modified algae and cyanobacteria. Both presentations can be downloaded from my SlideShare site, at the following links:

Government Regulation of Synthetic Biology: is the existing framework sufficient to address uses of SynBio in industrial biotechnology?

The Emerging Roadmap to Gain Regulatory Approvals for Uses of Genetically Modified Algae in Biofuel or Bio-Based Chemical Production

As I learn more about EPA’s intentions, I’ll post a more comprehensive summary and analysis of the project and its goals. Among the questions that come to mind are how will EPA define “synthetic biology” (a term which has been defined in many different ways by different observers in recent years) and what extra data might the agency require in the new guidance document for organisms falling into that category; why are they singling out algae/cyanobacteria and what additional data requirements might there be; and whether EPA’s concerns for algae relate primarily to possible open-pond uses of GM algae rather than contained uses.

White House Initiative to Update the Coordinated Framework

One thing that seems clear is that this action by EPA was triggered, at least in part, by the other recent development on the U.S. federal biotechnology scene. On July 2, 2015, the White House announced that it had issued a memorandum to the heads of the EPA, the U.S. Department of Agriculture, and the Food and Drug Administration, directing these agencies to begin a review of their biotechnology regulations under the 1986 “Coordinated Framework”, to determine whether revisions, updating, or other changes might be needed in view of new technologies and other developments since the adoption of the framework. As stated in the memorandum, the goals are “to modernize the Federal regulatory system for the products of biotechnology and to establish mechanisms for periodic updates of that system”.

This announcement is described in a page on an OSTP blog, and the agency memorandum itself can be found here. The memorandum, while asserting that the federal framework has provided effective management of health and safety risks, cites “unnecessary costs and burdens” that have in some cases arisen from jurisdictional uncertainty and unpredictable review timeframes, and that these have particularly disadvantaged small to mid-size companies. The memo also mentions the need to update the Framework in view of advances in science and technology that have been developed since its publication and 1992 revision.

The memorandum describes the formation of a new Biotechnology Working Group under the Emerging Technologies Interagency Policy Coordination Committee (ETIPC), which will carry out the activities mandated by the memo. Specifically, the Working Group has been tasked with developing an updated and clarified Coordinated Framework within one year, including a mechanism for regular reviews and updates of the Framework; developing a long-term strategy to ensure that the Framework is equipped to adequately assess risks without undue burdens on the regulated community; and producing annual reports on its activities for at least the first five years. The memo also directs EPA, USDA and FDA to commission an external, independent assessment of the possible future landscape of biotech products, to be sure that the Framework is equipped to deal with any potential risks posed by such developments.

The specific responses and actions of the agencies and the new Working Group will become more clear in the coming weeks. However, it appears that EPA’s action of last week is one component of that agency’s response to the White House directive. Even earlier, the USDA announced its intention to again revisit the scope of its biotechnology regulations, by formally abandoning a proposed rule for this purpose issued in 2008 and soliciting public comment on ideas for restarting such an effort, in a comment period that closed earlier this summer. That ongoing effort will presumably also take place under the new White House directive.

It’s hard to argue against the idea that, after almost 30 years under the original Coordinated Framework, it’s time for a review of its suitability and relevance in view of the significantly-improved and more powerful genetic technologies now available and in light of how biotechnology-dependent industries have evolved during that time. However, there is always the risk that opening such a comprehensive review of the existing framework might have unintended consequences or give rise to a new round of public concerns (whether or not promoted by activist groups) over the safety of the technology, especially when most observers agree that the existing framework largely continues to operate as originally intended and is doing a good job of assessing and managing risks. Here too, I plan to shortly post a more comprehensive summary of the White House’s action and an analysis of its implications for biofuel and bio-based chemical manufacture.

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.