Slides Posted from BIO World Congress Presentation on Updating U.S. Biotechnology Regulations

I’ve posted my slides from my presentation last month at the 2016 BIO World Congress on Industrial Biotechnology. My talk was entitled “Updating the Coordinated Framework: What does it mean for biofuels and bio-based chemicals?”, and you can find the slides here.

The presentation described the ongoing effort, initiated by the White House in July 2015, to review and update (“modernize”) the federal government’s Coordinated Framework for Biotechnology Regulation, which has been in place since 1986 with only relatively minor revisions since that time. Since beginning this effort in July, the White House Office of Science and Technology Policy (OSTP) has convened an interagency Working Group, it has coordinated several public meetings to discuss the Framework and how it regulates biotech products, and it has commissioned the National Academy of Sciences to conduct a study predicting the future landscape of biotechnology products. In addition, both EPA and USDA have held public hearings and/or public comment periods on specific topics within their biotechnology regulatory programs.

Although this interagency effort remains in progress, the original charge from the White House was to come up with results and recommended changes to the Framework within one year. OSTP says it will meet this goal by publishing its recommendations and any proposed revised regulations by the summer of 2016. Until then, it is hard to know exactly what will be the result of the process, but in my talk, I predicted the outcomes would include:

  • Few, if any, significant changes in agency regulations that might affect industrial biotechnology, other than the possibility of substantial revisions to the USDA biotechnology rules to broaden their scope to allow the agency to assess noxious weed risks and other potential ecological impacts.
  • Clarification of how new technologies such as synthetic biology, gene-editing methods like CRISPR, and other new tools of biotechnology might be treated under the agency regulations in the Framework.
  • Greater communication and coordination between the agencies, including the possible creation of a central clearinghouse for regulatory information.
  • The possibility that the agencies may need to address the substantial volume of comments that can be expected from the sector of the general public opposed to some aspects of biotechnology, and the risk that this could lead to stricter biotechnology regulations, particularly in agriculture and foods.
  • The likelihood that industrial biotechnology will be impacted to a greater extent by other regulatory changes, such as the political fate of the Renewable Fuel Standard, the possible (although likely limited) impact of any TSCA reform bill that Congress may pass, and the ongoing efforts by FDA and the Association of American Feed Control Officials to better harmonize their review processes for new animal feed ingredients.

I’ll report on any further developments in this process as they occur later this 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. Please visit our other blog, Biofuel Policy Watch.

 

 

Joule’s ethanol pathway approved by EPA under the RFS

Developers of novel renewable fuels or new methods of manufacturing biofuels may need to obtain EPA approval for their production pathway in order to qualify to generate Renewable Identification Numbers (RINs) under the U.S. Renewable Fuel Standard (RFS). This is a topic I’ve covered in several previous blog entries, particularly in 2014 when EPA revised its procedures and guidelines for submitting petitions for new pathway approvals. Briefly, if a fuel is produced by a pathway that is not already qualified under the RFS regulations, the developer must submit a detailed petition to the Agency describing the process to substantiate that it meets the requirements of the law, including achieving the applicable threshold of reduction of greenhouse gas (GHG) emissions.

I’m happy to report the success of one petition process with which I’ve been involved. Joule Unlimited Technologies recently announced that it received EPA approval for its Sunflow®-E ethanol process as an advanced biofuel, thus qualifying the pathway to generate advanced biofuel (D-5) RINs. To make its Sunflow-E ethanol, Joule converts CO2 to ethanol directly in a continuous process, using engineered bacteria as living catalysts. To qualify for the category of “advanced biofuels” under the RFS, the production pathway must reduce lifecycle GHG emissions by more than 50% when compared to traditional petroleum based fuels. In the EPA’s analysis of Joule’s petition, Joule’s Sunflow-E was found to reduce lifecycle GHG emissions by 85%, significantly above the required threshold.

Working as a consultant to Joule, I was the company’s liaison to EPA throughout this petition process, and I helped coordinate the in-house work of a very talented and dedicated technical team to draft the petition and to make this approval possible.

EPA’s approval letter of the Joule pathway can be found on EPA’s website. You can see Joule’s press release for more information on Joule and the Sunflow-E ethanol process. Please contact me if you have any questions or would like assistance with any matter relating to the Renewable Fuel Standard or other renewable fuels-related issue.

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. Please visit our other blog, Biofuel Policy Watch.

I’ll be speaking at the 2016 BIO World Congress next week

I will be in San Diego this April 17-20 for the BIO World Congress on Industrial Biotechnology to moderate and speak on the panel “Regulatory Growth and Commercial Development in Alternative Feedstocks and Algae. My talk will provide an update on the ongoing U.S. federal government efforts to update and modernize the Coordinated Framework for Biotechnology Regulation. As always, I’ll be posting my slides online after the conference.

The BIO World Congress provides 3 days of robust programming, networking and partnering meetings via the BIO One-on-One Partnering™ System. According to BIO:

  • 50% of attendees are international, coming from 30+ countries
  • 30% of attendees are NEW industry professionals attending the event for the very first time
  • 40% of attendees are C-Level or VP-level + hundreds of speakers.

There will be over 100 sessions featuring industry thought leaders in plenary sessions, breakout sessions across 8 dedicated tracks, GreenTech Investor sessions, an IP Symposium (new in 2016) and dedicated workshops. The conference affords an opportunity to catch up with colleagues, make new connections, and enjoy the networking opportunities at ten dedicated receptions, refreshment breaks, and other events throughout the week.

Here are some useful links:

Email worldcongress@bio.org if you have questions. Hope to see you in San Diego!

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.

Comments Submitted on USDA Biotech Regulations

I’ve just submitted comments in response to the recent notice from the USDA Animal and Plant Health Inspection Service (APHIS) requesting public comment on certain questions relating to the agency’s biotechnology regulations. On February 5, 2016, APHIS published a notice in the Federal Register (81 FR 6225-6229, Docket No. APHIS-2014-0054) stating its decision to complete a programmatic environmental impact statement (EIS) in connection with the revisions and amendments to the biotechnology regulations that are under consideration at the agency. According to APHIS, these proposed revisions primarily consist of amendments to its regulations covering introductions into the environment of genetically modified plants and agricultural microorganisms, in order to address advances in biotechnology and issues raised by stakeholders. The APHIS notice described the range of proposed alternatives that are currently under consideration for evaluation in the EIS, and the agency requested public comment on these and other issues.

The APHIS biotechnology rule (7 CFR Part 340) is the primary U.S. regulation that has governed the agricultural biotechnology industry. Although having its primary impact on agricultural crops, this rule would also potentially apply to any developer of transgenic plants to be used as feedstocks for the production of biofuels or bio-based chemicals. Although not explicitly stated in the agency’s posting, this action is taking place at the same time all federal agencies have been directed by the White House to reexamine their biotechnology regulatory policies under the Coordinated Framework (see my August 5, 2015 post and other recent posts on the blog), and so any changes APHIS may propose to its regulations might be adopted within the overall time frame of the White House effort.

My comments touched on the following points:

  • The existing APHIS regulations under 7 CFR Part 340 have been successful, and there have been no demonstrable adverse effects arising from plants or microorganisms subject to the regulations, in spite of the allegations or concerns of biotech critics and other observers.
  • APHIS has gained a considerable knowledge base and expertise in the review of the environmental impact of modified plants and agricultural microorganisms.
  • Nevertheless, it is appropriate for USDA to review the scope of the Part 340 regulations, and to consider other revisions to the rules, in view of changes in statutory authority, advances in technology, and the agency’s years of experience in regulating agricultural biotechnology.
  • I expressed support for one of the alternative regulatory approaches proposed in the APHIS Federal Register notice, which it appears APHIS would use to establish categories of activities or articles not needing prior APHIS review or notification at any level of use.
  • I further suggested that any revision to the regulations should include a provision under which almost all small-scale research field tests can take place without prior APHIS notification, as long as the test follows accepted performance standards, perhaps subject only to a simple online registration.

It is very hard to predict what will come of this effort. USDA has tried once before to revise the Part 340 regulations, by publishing a proposed revised rule in 2008 which was eventually withdrawn from consideration. The agency received more than 88,000 comments on that proposed rule. Although no detailed explanation was given for the decision to withdraw, my guess is that USDA found itself torn between competing objectives. On the one hand, the agency wanted to strengthen the scientific basis for its reviews of proposed field activities by more formally allowing the consideration of noxious weed risk and other ecological issues, in response to critics and biotech opponents that had questioned the adequacy and scope of APHIS’s environmental reviews. But on the other hand, there was likely strong sentiment within the regulated community that field testing and other activities with the more familiar crop species should be deregulated in whole or in part, based on the significant accumulated experience with such species. I suspect that, especially in view of the avalanche of public comments it received, the agency was not able to navigate between these two competing objectives. The same dynamic may arise in the current attempt as well.

Please contact me to obtain a complete copy of my comments, or with any questions you may have about this process. The comment period has been extended until April 21, 2015, and comments can be submitted at http://www.regulations.gov/#!docketDetail;D=APHIS-2014-0054.

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. Please visit our other blog, Biofuel Policy Watch.

 

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.