Regulation of Cell-Based Meats: Follow-up and New Developments

This post continues the series of discussions, beginning with an August 20, 2018 entry, on regulatory 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. I submitted comments to the U.S. FDA on September 24, 2018, during the open-comment period that followed the Agency’s July 12, 2018 public meeting on this topic. My comments were based on, and expanded on, the themes discussed in the previous posts. You can access a copy of my complete comments here, but the following is a summary of the points I raised:

  • Production of foods from animal cell culture can be carried out using well-established, reproducible and predictable methods, that can lead to safe, sanitary production of nutritious foods for U.S. consumers, that could even be safer than existing practice.
  • There is a long history of the safe use of animal cell culture for research and other purposes, which provides a sound basis for adoption of safe techniques for producing human food through cell culture.
  • If a premarket review program is to be established, I recommended that it be based on existing law and regulations to the greatest extent possible. FDA should be the lead agency for any program, and the agency should utilize the existing GRAS Notice program, which has worked extremely well to allow reviews of innovative new food ingredients, or to establish a parallel, but similar program for cell-based meats. Any such program should primarily focus on the composition, safety and nutritive value of the end product, although information about manufacturing methods must be part of the technical review.
  • I recommended that FDA should coordinate its efforts with the U.S. Department of Agriculture, to be sure that USDA’s scientific expertise is utilized in any reviews carried out by FDA, and that cell-based meats are subject to existing or amended USDA regulations for sanitary production, facility inspection and labeling, for those foods (meats, poultry and catfish) that are within current FSIS jurisdiction. Both agencies should strive to avoid any jurisdictional battles that would create uncertainty that could stifle an innovative, emerging industry.

As of this writing, FDA received 477 comments on regulations.gov in response to this request. I have not studied these in detail, except to note that they were submitted by a broad range of commenters from industry, academia, NGOs and public interest groups, and also from private citizens. A number of private citizens submitted comments in favor of the development of “clean meat” and for FDA’s role in regulation, while there were also a good number of letters from private citizens opposing a regulatory scheme where FDA was the sole agency, and advocating for a role for the USDA. These latter submissions were all identical, as is often the case with agency public comments, and likely originated from the beef industry. Among the public interest group submissions were comments from animal rights groups, favoring the development of cell-based meats as an alternative to the consumption of animals.

In another related development, on September 13, 2018, the USDA published a notice in the Federal Register announcing that it and FDA will jointly hold a two-day public meeting October 23-24 on cell-based meats. This meeting will focus on several specific questions relating to jurisdiction, potential risks posed by the manufacturing process, provisions for facility inspection and product labeling, among others. Public comments on these topics will be accepted through November 26, 2018. I am making plans to attend the first day of this meeting, which will feature discussion of issues pertaining to potential risks and agency oversight, and afterwards I hope to report on the outcome of the meeting.

Finally, there was an interesting article in Monday’s New York Times about the efforts to develop cell-based production processes to manufacture kosher pork products. No mention of regulatory issues, but interesting speculation about what would be needed for a cell-based meat product or its production process to be certified to be meat-free and therefore “pareve” under Jewish kosher law.

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.

 

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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.

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.