Regulation of Cell-Based Meats: Comments on an Appropriate Regulatory Framework

As discussed in a previous post in the blog, the U.S. Food and Drug Administration has requested public comment on issues relating to the anticipated introduction of human food products produced from cultured animal cells (“cell-based meat” products), as replacements for traditional meat, poultry or fish or other products of traditional animal agriculture. Then, in a second post, I provided my thoughts on the scientific issues related to this emerging industry sector, including comments in response to the four questions FDA posed in its June 2018 Federal Register notice.  In today’s blog entry, I offer my perspective on the regulatory and jurisdictional issues that may arise if the U.S. government decides to institute regulatory oversight over products in this sector.

Although FDA did not explicitly ask for public comment on such issues, I feel it would be appropriate for stakeholders to comment on what would be the best or most optimum regulatory structure in the United States for oversight over cell-based meat. As noted in my first post, battle lines are already being drawn between those preferring FDA to have the lead in such regulation and those preferring that the U.S. Department of Agriculture (USDA), through its Food Safety and Inspection Service (FSIS), have the lead role. I believe that there is a role for both agencies, and that any regulatory regime include participation from both agencies in a collaborative manner, as has been done many times before, in the regulation of biotechnology and other industries.

Specifically, FSIS’s role is to ensure the safety and wholesomeness of the nation’s meat, poultry and egg products through its inspection and labeling programs. Its mission statement is “Protecting the public’s health by ensuring the safety of meat, poultry, and processed egg products.” FSIS regulations under the Federal Meat Inspection Act and the Poultry Products Inspection Act are found in 9 CFR Subchapter E, Parts 412-500, and its regulations for egg product inspections are at 9 CFR Subchapter I, Parts 590-599.  Note that FSIS has no authority over fish products, except for catfish, for which FSIS maintains regulatory programs similar to those for meat under 9 CFR Subchapter F, Parts 530-561. FSIS’s regulations include rules governing the safe, sanitary and humane slaughter and processing of food animals, and a robust inspection program under which slaughterhouses and food processing facilities are overseen by federal inspectors and must follow detailed sanitation requirements under 9 CFR Part 416. Part 424 of the regulations contains a lengthy list of ingredients that can be used in meat processing and/or which can appear in meat products. FSIS has also developed test methods for certain food pathogens like the most virulent E. coli strains, and also requires product labels to be approved under 9 CFR Part 412. A good, detailed overview of the system of U.S. regulation of meat and other foods can be found at a North Dakota State University website; another useful site is one posted by Cooperative Extension, focusing on regulation of meat processing.

As effective as this program has been, there are two difficulties in extending this regulatory regime to oversight over cell-based meats. First, the FSIS regulatory program stems from the definition of “meat product” in the Federal Meat Inspection Act (FMIA), which is:  “any product capable of use as human food which is made wholly or in part from any meat or other portion of the carcass of any cattle, sheep, swine, or goats, excepting products which contain meat or other portions of such carcasses only in a relatively small proportion or historically have not been considered by consumers as products of the meat food industry …” (emphasis added). Lawyers may long debate whether animal cells that have been grown in culture for multiple generations can be considered to have originated from an “other portion of the carcass”, especially if the cell line was originated with cells from a live animal rather than a dead animal. Based on this language, it would seem likely that regulatory changes, if not an amendment to the legislation, might be needed to unequivocally bring cell-based meat products under the jurisdiction of the FMIA as a “meat product”.

On the other hand, although the definition of “meat product” in the regulations, at 9 CFR 301.2, parallels the definition in the legislation, the regulations also define “meat byproduct” as “Any part capable of use as human food, other than meat, which has been derived from one or more cattle, sheep, swine, or goats …” (emphasis added), without mention of a carcass; and “meat byproduct” is included in the definition of “product” in the regulations. One might therefore argue that cell-based meats could be subject to the FMIA as “meat byproducts”, and that is indeed the position taken by the National Cattlemen’s Beef Association, in a statement issued before FDA’s July 12, 2018 public meeting (although this association’s persistence in calling the new products “fake meat” is frankly not helpful to foster a reasoned public debate). It seems to me that this would be a somewhat tortuous way to achieve regulatory coverage for these products, and manufacturers would not want their products to have to be labeled as “meat byproducts” (although, again, that might satisfy the political goals of the traditional meat industry).

Second, FSIS has not, historically, maintained any program of premanufacture review of the safety of meat or its ingredients. Its regulatory oversight is based on the assumption that as long as meat is obtained from healthy animals and is processed under the appropriate sanitary conditions and is appropriately labeled, meat products are safe to eat. It is not clear whether USDA FSIS has the required staff or expertise to conduct science-based premarket reviews of the safety of new meat products in a timely manner.

FDA, on the other hand, has long had as part of its mission the requirement to review the safety of proposed new food ingredients, although I should note that U.S. law does not require premarket approval of “foods” per se. Companies can introduce and sell new food products without oversight, as long as they are not “adulterated” or do not include new ingredients not already approved for use in food: such new ingredients would be regulated as food additives unless they can be shown to be Generally Recognized as Safe (GRAS). I have previously described FDA’s GRAS Notice program and the 2016 Final Rule that established this program in previous posts on the blog, most recently in January 2018; with more information available on FDA’s website. Under this rule and its predecessor interim policy, FDA has reviewed hundreds of new food ingredients in a timely and professional manner. .

To the extent that premarket review for cell-based meat products is deemed to be needed or desirable, I suggest an approach along the following lines. FDA’s Center for Food Safety and Nutrition (CFSAN) should be responsible for premarket review, under its existing GRAS Notice program or a by creating a new parallel (but similar) process. Manufacturers would submit dossiers to FDA supporting the safety of their product, and I suggest that the main focus of FDA’s review should be to assess the equivalence of the product to traditional meat products from a nutritional and safety perspective, while also assessing the safety of the manufacturing process and the ingredients used in food production. In other words, the developer of a product produced from animal cell culture should not have to demonstrate safety de novo, i.e. through extensive toxicology or other testing, but instead should be able to show that the product has equivalent nutritional value to traditional products, has no unwanted impurities or byproducts as a result of its production method, and is chemically or compositionally equivalent to the comparable existing product. Manufacturers should also be required to follow Good Manufacturing Practices and other procedures as mandated under current food safety law (e.g. the Food Safety Modernization Act). My preference would be a program like the GRAS Notice program, where FDA review is encouraged but not mandatory; or if mandatory that provision be made for expedited review of follow-on products having only minor differences from originally-approved products.

In establishing such a program, FDA should make use of available scientific expertise, including from academia, industry and importantly also from within the USDA, particularly within FSIS, to ensure that the best and most appropriate technical knowledge is applied to premarket safety assessments. Then, once a product is approved for marketing or otherwise clears FDA’s review process, the traditional inspection and oversight authority of FSIS could come into play. New procedures would need to be established for oversight, inspection and registration of cellular production facilities, analogously to existing oversight of meat processing plants, and this might require revisions to FSIS regulations, for example, to define revised sanitary and other procedures and safeguards applicable to cell culture, and possibly also to provide for the inspection of final products and their labeling. USDA should retain its labeling authority under the FMIA regulations; but I won’t comment on the important question of whether these products should or should not be labeled as “meat”.

Whenever a new technology emerges that may lead to novel, paradigm-breaking products, it is inevitable that regulatory turf wars will arise or loom on the horizon. It’s also inevitable that the existing industries that are threatened by the new products close ranks and, where possible, use existing regulatory barriers to make life difficult for what they see as upstart competitors. In fact this is far from the first time in the history of the biotech industry that battles over regulatory jurisdiction have occurred, most notably for oversight over pest-resistant GMO crop plants and certain other agricultural products, but these disputes have always been satisfactorily resolved. I hope that FDA and USDA are able to amicably work together to establish a reasonable regulatory framework that assures the public that these new products are safe and nutritious to eat, without imposing an unnecessary burden or punitive regulatory barriers on the innovative companies developing such products.

D. Glass Associates, Inc.is a consulting company specializing in government and regulatory affairs support for renewable fuels, industrial biotechnology and related field. 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.

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Regulation of Cell-Based Meats: Scientific Issues

As discussed in the previous post in the blog, the U.S. Food and Drug Administration has requested public comment on issues relating to the anticipated introduction of human food products produced from cultured animal cells (“cell-based meat” products), as replacements for traditional meat, poultry or fish or other products of traditional animal agriculture. The following are my thoughts on the scientific issues related to this emerging industry sector, including responses to the four questions FDA posed in its June 2018 Federal Register notice,

FDA’s questions largely asked commenters for input as to whether the anticipated production methods for cell-based meats would raise safety concerns, and in particular whether they might raise concerns different from those applicable to traditional meat products. In fact, some of the questions, notably the fourth, can be viewed as suggesting that commenters provide evidence for why the new methods might be safer than existing practice, rather than riskier. There is some overlap between their questions, and so I first offer the following general comments, which may be applicable to more than one of FDA’s questions. These comments assume that, as a result of this public comment process, FDA will put in place some form of premarket review for cell-based meat products, although that is far from a certainty, and my comments should not necessarily be construed as favoring such an outcome.

  • Production of foods from animal cell culture has the potential to be more reproducible and predictable than manufacturing meat products by growing and slaughtering animals. Once each producer develops and optimizes its production method, it is expected that the methods will be carried out under suitable Good Manufacturing Processes, including Standard Operating Procedures and appropriate QA/QC methods. Companies would use food-grade ingredients (e.g. the components of cell growth media) that are well-studied and known to be safe. Production would take place under well-understood protocols where temperature and sanitary conditions could be better controlled; and the need for aseptic techniques would minimize the possibility of contamination by pathogens.
  • There is a long history of use of animal tissue culture cells in research and for commercial purposes such as pharmaceutical production. Although such activity has been carried out for purposes different from food production, this experience provides basic guidance for how animal cell culture work can be carried out safely, to avoid adverse occupational health effects, other public health concerns, and any possible environmental risks. There are several articles in the literature dealing with the safety aspects of animal tissue culture research. One example is a recent review (Herman and Pauwels, 2015), which describes the potential health and safety risks to consider when working with animal cell culture (e.g. the potential for microbial contamination) as well as the types of procedures and practices that can be used to minimize such risks. Presumably commenters will bring these and other references to FDA’s attention during the comment period.
  • In many cases, production of meat products via cell culture would avoid contamination that is currently possible from environmental or other inputs: e.g., meat products would not require the massive use of antibiotics now common in animal agriculture, and fish products would be free from contamination from mercury, plastics and other potentially-hazardous materials present in oceanic or river environments.
  • In the case of fish, cell-based methods would eliminate the need for fish flesh to be maintained on ice for hours or days from the time of fish catch to the time of processing.

To address FDA’s specific questions (paraphrased or excerpted):

What considerations specific to animal cell culture technology would be appropriate to include in evaluation of food produced by this method of manufacture?

Although the focus of regulation should be on the end product, and in particular its comparison to traditional meat products, it is appropriate for FDA to review manufacturing information as part of any premarket assessment it may institute. Such information might include the identity, the original source, and characterization of the cell lines used, the methods and growth conditions used for cell culture, the components of the culture media used to grow the cells, and any downstream processing steps. Manufacturers should ascertain that cell lines and the resulting product are free of viruses or any contaminating microorganisms, as well as any other contaminants.

What kinds of variations in manufacturing methods would be relevant to safety for foods produced by animal cell culture technology?

To some extent, an answer to this question is the same as for the first question. However, a response to this question could be that cell culture manufacturing methods hold the potential to be more predictable, more reproducible, more sanitary and therefore safer than traditional methods involving the slaughter of animals, for the reasons discussed above. Use of cell culture as a manufacturing method would not necessarily create new potential risks, but could in fact reduce or eliminate risks of existing food processing. In addition, any regulatory scheme should provide an expedited path to market when minor manufacturing changes are proposed for products already reviewed and cleared for human consumption.

What kinds of substances would be used in the manufacture of foods produced using animal cell culture technology and what considerations would be appropriate in evaluating the safety of these uses?

Detailed responses to this question would need to be addressed by each individual manufacturer, but FDA’s assessment should be no different than current practice in evaluating foods or food additives produced by biological processes like microbial fermentation. In such assessments, FDA requests information on the components of fermentation media and other inputs into the process, and generally requires that all such substances be food-grade and of suitable purity. Specific ingredients in animal cell culture may require some additional scrutiny or require efforts from industry to develop or source food-grade replacements. Any ingredients that are not food-grade may need to be replaced. That being said, the focus should be on the final, finished product, and whether the substances used in processing are present in the product, and if so, whether such presence poses any health or safety risks.

Are the hazards associated with production of foods using animal cell culture technology different from those associated with traditional food production/processing (such as, for example, insanitary conditions, improper temperature controls, or control of contaminants)? Is there a need for unique control measures to address the hazards associated with production of foods using animal cell culture technology?

This question is addressed by the general comments above. It is very likely that fewer potential risks would arise from producing foods using cell culture compared to traditional methods. The control measures that might be needed for cell-based manufacture would be similar to those commonly used in the microbial fermentation industry, but would likely need to be different from those now imposed on traditional meat production (e.g. under USDA’s sanitation regulations).

I am planning to use this blog post as the starting point to draft and submit my comments to FDA by the September 25, 2018 due date, as requested at the docket for this matter at regulations.gov, but I welcome any feedback or comments anyone may have on these issues.

In the post that follows, I’ll offer some comments on what might be an appropriate regulatory scheme for cell-based meat products.

D. Glass Associates, Inc.is a consulting company specializing in government and regulatory affairs support for renewable fuels, industrial biotechnology and related field. 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.

Cell-Based Meats: Regulatory Issues Facing an Emerging Field

Although a bit off-point from the original scope of this blog (biofuels and bio-based chemicals), I’ve lately been spending some time with the emerging field of cell-based meats, which has in recent months caught the attention of federal regulators here in the U.S. This field, more formally known as “foods produced using animal cell culture” or also as “cellular agriculture,” involves R&D aimed at producing edible substitutes for common human foods through cell culture, rather than through the farming and/or slaughter of live food animals (one early summary of the field can be found here). There are a growing number of companies in the U.S. and elsewhere, as well as numerous academic groups, that are working on such technologies, with the goal of creating beef, pork, poultry or fish products grown from tissue culture. Also under development are products such as egg substitutes comprised of microbially-produced proteins, as well as the “Impossible Burger” where a yeast-produced plant heme protein gives veggie burgers the taste and feel of beef hamburgers.

Although there have been low-key internal discussions within regulatory agencies and individual one-on-one discussions between companies and regulators about the appropriate regulatory pathways for such products, recent events in the first half of 2018 have brought this issue to the forefront. These have included a petition filed in February 2018 by the U.S. Cattleman’s Association asking the U.S. Department of Agriculture (USDA) to block cell-cultured meat products from being labeled as “meat” or “beef” (similar to the unrelated, recently-successful effort to prevent soy- or nut-based products from being labeled as “milk”), a Congressional briefing on the subject of cellular agriculture in June 2018, and a public meeting held by FDA on July 12, 2018 to discuss scientific issues relating to safety and regulatory oversight over such products (see below). Also, although not directly related to the use of tissue culture to produce meat substitute products, in July 2018, the FDA informed Impossible Foods, Inc. that the Agency had no objections to the company’s finding that its microbially-produced soy leghemoglobin was Generally Recognized as Safe for use with its plant-based Impossible Burgers.

FDA’s interest in regulating these products is notable because historically, the regulation of meat products in the U.S. has been under the auspices of the USDA, through the inspection and labeling authorities of its Food Safety and Inspection Service (FSIS). Indeed, the battle lines are beginning to be drawn between those favoring FDA’s having the lead role through its traditional responsibility for reviewing the safety and efficacy of new food additives and ingredients, and those who would prefer to see jurisdiction for meat and poultry to remain with the USDA (cell-based fish products, however, would be on the sidelines of any jurisdictional battle, because USDA has no regulatory or inspection role for any fish products other than, through a legislative quirk, catfish). FDA says that it has been in discussions with USDA about coordination to avoid any possible regulatory overlap, although there are signs that each agency may be pursuing its own plans for regulatory programs.

It was with this backdrop that FDA held its public meeting on July 12, 2018. The stated goal of the session was to “provide the public the opportunity to provide comments related to the production of foods using animal cell culture technology”. The June 18, 2018 Federal Register Notice announcing the meeting listed four topics on which public comments were invited:

  • FDA has evaluated a variety of foods produced by cell culture, including microbial (g.,probiotics), algal (e.g., spirulina), and fungal products (e.g.,mycoprotein). What considerations specific to animal cell culture technology would be appropriate to include in evaluation of food produced by this method of manufacture?
  • FDA has issued guidance on how to assess the effects of significant manufacturing process changes on the safety of a food ingredient. What kinds of variations in manufacturing methods would be relevant to safety for foods produced by animal cell culture technology?
  • FDA has a variety of pre- and postmarket programs for evaluating the safety of substances used in the production and manufacture of foods, including, for example, food additive and color additive regulations and preventive control requirements. What kinds of substances would be used in the manufacture of foods produced using animal cell culture technology and what considerations would be appropriate in evaluating the safety of these uses?
  • Are the hazards associated with production of foods using animal cell culture technology different from those associated with traditional food production/processing (such as, for example, insanitary conditions, improper temperature controls, or control of contaminants)? Is there a need for unique control measures to address the hazards associated with production of foods using animal cell culture technology?

I was not able to attend the meeting myself, and so I can’t summarize the meeting and the nature of the public comments delivered orally at the session. There are several excellent summaries available online, such as reports on the websites of the Food and Drug Law Institute, the Good Food Institute and Ag Funder News. In the public meeting, FDA officials laid out the scientific issues it anticipates being raised by products in this category. In addition to hearing public comments from industry, public interest groups and others, the meeting featured a panel of stakeholders from industry, academia, and the non-profit sector offering their perspective on these issues and the nature of the regulatory regime that might emerge.

Following the meeting, FDA is soliciting public comments through September 25, 2018, which can be submitted online at regulations.gov, or in writing to FDA’s Rockville, MD address.

In follow-up posts, I have offered my thoughts about the scientific questions FDA has posed, and the regulatory and jurisdictional issues that should be addressed to enable the adoption of a rational, science-based regulatory scheme that utilizes all the applicable resources of federal regulatory agencies to assure the public that cell-based foods are safe, without creating an undue burden on the innovative companies developing these products.

D. Glass Associates, Inc. is a consulting company specializing in government and regulatory affairs support for renewable fuels, industrial biotechnology and related field. 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.

 

 

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

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

As discussed in more detail in my earlier blog posts in 2013 and 2015, under the Federal Food, Drug and Cosmetic Act, most new substances that are intended to be components of food or to affect components of food are considered to be “food additives” and would ordinarily need to be approved through the submission of a Food Additive Petition.  However, the law further provides that “substances that are generally recognized, among experts qualified by scientific training and experience to evaluate their safety as having been adequately shown …  to be safe under the conditions of their intended use,” are not considered as food additives. This is the category of substances known as GRAS: “generally recognized as safe”. Certain substances were “grandfathered” in as GRAS at the time of the legislation based on common prior safe use in foods, and other substances were later affirmed by FDA to be GRAS, often in response to manufacturer petitions. In addition, under the law, manufacturers are allowed to self-certify that a product or food additive is GRAS, and many companies have historically taken this route.

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

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

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

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

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

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

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

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

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

D. Glass Associates, Inc. is a consulting company specializing in government and regulatory affairs support for renewable fuels and industrial biotechnology. David Glass, Ph.D. is a veteran of over thirty years in the biotechnology industry, with expertise in industrial biotechnology regulatory affairs, U.S. and international renewable fuels regulation, patents, technology licensing, and market and technology assessments. More information on D. Glass Associates’ regulatory affairs consulting capabilities, and copies of some of Dr. Glass’s prior presentations on biofuels and biotechnology regulation, are available at www.slideshare.net/djglass99 and at www.dglassassociates.com. The views expressed in this blog are those of Dr. Glass and D. Glass Associates and do not represent the views of any other organization with which Dr. Glass is affiliated.

MCANs Reviewed by EPA Since 2016 TSCA Reform

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

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

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

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

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

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

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

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

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

 

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

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

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

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

D. Glass Associates, Inc.is a consulting company specializing in government and regulatory affairs support for renewable fuels and industrial biotechnology. David Glass, Ph.D. is a veteran of over thirty years in the biotechnology industry, with expertise in industrial biotechnology regulatory affairs, U.S. and international renewable fuels regulation, patents, technology licensing, and market and technology assessments. More information on D. Glass Associates’ regulatory affairs consulting capabilities, and copies of some of Dr. Glass’s prior presentations on biofuels and biotechnology regulation, are available at www.slideshare.net/djglass99 and at www.dglassassociates.com. The views expressed in this blog are those of Dr. Glass and D. Glass Associates and do not represent the views of any other organization with which Dr. Glass is affiliated.

 

 

Summary of EPA’s October 27, 2016 Engineered Algae Public Meeting

On October 27, 2016, the U.S. Environmental Protection Agency convened an open meeting to begin soliciting public comment on its recently-issued draft guidance for the preparation of TSCA biotechnology submissions involving genetically modified algae or cyanobacteria. The agenda for the meeting can be found here, and the Draft Algae Guidance can be downloaded here. The charge questions and other supporting material for the meeting are available here. The meeting also served as the kickoff for a public comment period that runs until November 30, 2016.

The meeting took place at Arizona State University in Tempe, following the end of the Algae Biomass Summit which took place in Phoenix earlier that week. I attended the meeting via the live Web streaming that EPA and ASU arranged. The following is a brief summary of what I felt were the more important issues discussed.

The meeting began with brief presentations by EPA staff on the TSCA biotechnology regulatory program, the process by which EPA conducts risk assessments under the program, and finally an overview of the contents of the Draft Algae Guidance document. This was followed by three opportunities for public comment: the first focusing on the Charge Questions that addressed algae ecological effects; the second focusing on the more general Charge Questions; and the third featuring comments on the Draft Algae Guidance itself.

Overall, I felt that this meeting featured more substantive discussion than what I recall was the case at the Agency’s September 2015 Washington, DC public meeting that kicked off their efforts to provide guidance for algae submissions under TSCA. Several commenters at last week’s meeting offered substantive observations or critiques of the Draft Algae Guidance document, and there were also some (predictable) comments from industry critics regarding safety and risk assessment. Among the key issues discussed:

  • There was some discussion of the impact of the Lautenberg TSCA reform legislation on the biotech program. EPA staff summarized the major impacts as the requirement that the agency issue definitive statement on the results of TSCA risk assessments (as opposed to previous practice of simply “clearing” PMNs and MCANs without making a statement on the assessed risk); and the need for the agency to make more information on such decisions available to the public (i.e. the policy of “transparency” which came up often in discussions). EPA has already begun implementing both these directives in its ongoing practice under TSCA.
  • Comments from industry critics (Friends of the Earth, Biofuel Watch, Consumers Union and the International Center for Technology Assessment) focused on the their contention that the environmental effects of GE algae were unpredictable, the alleged inability to contain the organisms even when cultivated in contained photobioreactors, and the critics’ desire to see EPA regulate all applications of synthetic biology under TSCA, even those limited to single nucleotide changes. Some suggested that EPA needed to broaden their risk assessments to consider the entire life cycle of the product and commercial process, rather than just the microorganism, although EPA staff felt this was beyond their authority under TSCA.
  • The critics were also unanimous in criticizing the extent of confidential information that is allowed in TSCA filings, which is then redacted in public documents.
  • Several of the critics also commented on EPA’s definition of “new microorganism” which limits its TSCA oversight to intergeneric organisms and thus excludes modified microorganisms which do not contain coding DNA from outside the host organism genus. Several speakers contrasted this definition to Footnote No. 1 in the OSTP July 2015 memo that kicked off the Coordinated Framework Modernization effort in which “biotechnology products” was defined more broadly. EPA staff explained that TSCA applies only to “new chemicals” that are not naturally occurring, and so the biotech program under TSCA was limited to “new microorganisms” that were judged to have been unlikely to have emerged through natural recombination at any time in evolutionary history.
  • Although the industry critics generally offered comments at every opportunity on a variety of topics, some of their comments showed a surprisingly poor level of knowledge about the TSCA regulations and their background. Several critics were confused about how the tiered exemptions work and were afraid that EPA would act unilaterally and rashly to add algae species to the exempt list (something EPA could do only through rulemaking, and only after conducting an exhaustive risk assessment).
  • There were a handful of academic scientists who offered substantive remarks on specific risk assessment issues. A speaker from Oklahoma State University made an interesting point, that algal blooms are usually a function of the prevailing environmental conditions rather than being determined by the biology of the strain(s) causing the bloom, so that a GE algae that escaped containment would not necessarily form a bloom itself and in fact would need to compete with better-established algae species and strains that were already adapted to the environment and perhaps even selected for bloom-forming traits.
  • Several speakers touched on substantive scientific topics about the content of the newly-released draft guidance document for algae, but it was difficult to have much to say about that guidance in a short 3-minute public statement, particularly when it had only been available for public review and comment for a short time.
  • Several industry speakers (e.g. representing Algenol, TerraVia, Synthetic Genomics, BIO and ABO) had kind words to say about EPA staff and their diligence in administering the regulations, and several stressed that going through the MCAN process is not easy and that EPA gives MCANs a thorough review. Industry speakers defended the need for strong CBI protection, while arguing that confidentiality claims are not necessarily asserted for the most important environmental data.
  • Industry speakers generally thought that the draft guidance was comprehensive and covered the major topics, although some worried that its comprehensiveness may give some observers the erroneous impression that all the data would always be needed for all submission. Suggestions were made to possibly institute tiered requirements depending on the familiarity of the host strain, and one industry speaker even suggested adding common algae strains to the list of hosts potentially qualifying for the tiered exemptions, a comment unlikely to be adopted, as discussed above.

Overall, I felt it was a useful and substantive meeting, and I think EPA got some useful feedback. Public comments will be entertained until November 30, 2016, after which the agency hopes to finalize the algae guidance document. I am planning to submit comments before this deadline, and I’ll report on future developments in the blog.

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.

 

EPA Public Meeting on Guidance for Algae Submissions

The Algae Biomass Organization recently announced that EPA will be hosting a public meeting entitled, “Opportunity for Public Comment on Algae Guidance for The Preparation of TSCA Biotechnology Submissions” in Tempe, AZ on October 27, 2016, immediately following the Algae Biomass Summit being held in Phoenix earlier that week. This meeting is to continue to seek public comment as EPA works on developing guidance for submitters of MCANs and other notices to EPA for the use of intergeneric algae for industrial purposes. EPA has not yet announced details of this meeting or its physical location, except that webcasting and teleconferencing will be available.

This meeting follows one that was held last year, also timed to coincide with the Algae Biomass Summit. I reported on that meeting from September 2015 in a previous blog entry, and I have also submitted comments to EPA during the public comment period that followed that meeting.

I’ll post updates as EPA provides more information about this meeting in the weeks to come.

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.