FDA’s Voluntary Consultation Program for Cultured Meat Products

From time to time on the blog, I’ve commented on the emerging field of foods derived from cultured animal cells, and how these products would be regulated by governments around the world. In today’s post, I’m catching up with some recent developments in the United States, relating to how the U.S. Food and Drug Administration (FDA) is carrying out its roles in oversight over such products.

As I reported back in 2018 in the blog, the FDA and the U.S. Department of Agriculture (USDA) issued a statement on November 16, 2018 to announce that the agencies would work together to develop a regulatory framework for cell-based meats. The statement said:

“Drawing on the expertise of both USDA and FDA, the Agencies are today announcing agreement on a joint regulatory framework wherein FDA oversees cell collection, cell banks, and cell growth and differentiation. A transition from FDA to USDA oversight will occur during the cell harvest stage. USDA will then oversee the production and labeling of food products derived from the cells of livestock and poultry.”

This was followed by a more formal agreement announced in March 2019, setting out agencies’ responsibilities in more detail. Among other responsibilities, it stated that FDA would maintain oversight over the initial processes of cell collection and growth, and in particular that the agency would “conduct premarket consultation processes to evaluate production materials/processes and manufacturing controls, to include oversight of tissue collection, cell lines and banks, and all components and inputs”.

I’m not aware of any subsequent formal announcement from FDA regarding a “premarket consultation process”, but in November 2022 the agency announced that it had reviewed the first product under such a program. In this announcement, the agency referenced the March 2019 USDA agreement, and said “The FDA’s approach to regulating products derived from cultured animal cells involves a thorough pre-market consultation process. While this is not considered an approval process, it concludes when all questions relevant to the consultation are resolved”.

FDA’s voluntary consultation program for human food made from cultured animal cells is described on its website. Although there does not appear to be a more definitive description of how a company would go about requesting voluntary consultation, the web page describes the process as follows:

The FDA’s voluntary pre-market consultation process evaluates the safety of food made from cultured animal cells before it enters the market. The pre-market consultation allows developers to work with the FDA on a product-by-product basis and informs them of issues they must consider to produce safe food that does not violate the Federal Food, Drug and Cosmetic Act’s requirements. As part of the pre-market consultation process, we evaluate the production process and the cultured cell material made by the production process, including the establishment of cell lines and cell banks, manufacturing controls, and all components and inputs. Our goal is to support innovation in food technologies while always maintaining as our priority the production of safe food.

We encourage firms to have conversations with us often and early in their product and process development phase. We are already engaged in discussions with multiple firms about various types of food made from cultured animal cells, including seafood and food destined for animal diets.

As of this date, two products have received “no questions” letters from the FDA under the voluntary consultation program: food products made from cultured chicken cells from UPSIDE Foods (November 2022) and GOOD Meat, Inc. (March 2023). In both cases, the agency posted on its website the nonconfidential version of the company’s original submission and any amendments, the agency’s “no questions” letter sent to the submitter, and a detailed internal FDA memo summarizing the basis for their finding.

According to FDA’s summary memos, the UPSIDE Foods product consisted of cultured Gallus gallus [chicken] cells, with characteristics of myocytes and fibroblasts, in the form of sheets of cells. The GOOD Meat product also consisted of cultured Gallus gallus cells, in this case derived from a commercially-available chicken cell line UMNSAH/DF1, with characteristics of fibroblasts. Unlike the sheets of cells used in the UPSIDE process, the GOOD Meat process uses a cell paste arising from the harvested cells. In both cases, FDA “evaluated information about the cell lines, the production process (including cell bank establishment), substances used in the production process, and properties of the harvested cell material, including information available in both the disclosable safety assessment as well as supporting, corroborative information in a confidential supplementary appendix”. For each product, FDA concluded that “based on the data and information presented in [the submission], we have no questions at this time about [the company’s] conclusion that foods comprised of, or containing, cultured chicken cell material resulting from the production process defined in [the company’s submission] are as safe as comparable foods produced by other methods”.

FDA’s Inventory page lists only these two submissions that have successfully completed FDA review. The site does not list, or indicate, whether there have been other submissions that are currently undergoing review, but it is reasonable to assume that there have been other submissions. One page on the FDA website says “We are already engaged in discussions with multiple firms about various types of food made from cultured animal cells, including seafood and food destined for animal diets”.

Although there does not appear to be any specific guidance for companies regarding how to prepare a dossier for consideration under this program, the agency’s website says that for questions about the pre-market consultation process for human food, companies should contact the agency’s Center for Food Safety and Applied Nutrition, Office of Food Additive Safety at AnimalCellCultureFoods@fda.hhs.gov. For cultured animal cell food products, or any of the byproducts generated during the production of process, intended for use in animal food, firms should contact the Center for Veterinary Medicine, Division of Animal Food Ingredients, at Animalfood-premarket@fda.hhs.gov.

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-five 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. In addition to his work as a consultant assisting industrial biotechnology companies prepare for and comply with government regulations, he has served as Director of Regulatory Affairs for Joule Unlimited Technologies and Vice President of Government and Regulatory Affairs for BioTechnica International. Dr. Glass has extensive experience with the biotechnology regulations of the U.S. EPA and other agencies, and has coordinated or assisted in the preparation and submission of 18 successful Microbial Commercial Activity Notices and several other biotechnology submissions in the U.S. and other countries. Dr. Glass holds a B.S. in Biological Sciences from Cornell University and a Ph.D. in Biochemical Sciences from Princeton University.

FAO Report on Safety Aspects of Cell-Based Foods

The Food and Agriculture Organization (FAO) of the United Nations has published a new report that comprehensively summarizes the state of the emerging field of cell-based or cultured food. The 146 page report, entitled “Food safety aspects of cell-based food” was issued by the FAO, in collaboration with the World Health Organization (WHO) in March 2023. This follows a 2020 report from the U.S. General Accounting Office on the regulatory framework for cell-cultured meat, which I described in an earlier post on the blog.

According to the FAO’s announcement, the new document “includes a literature synthesis of relevant terminology issues, principles of cell-based food production processes and the global landscape of regulatory frameworks for cell-based food production”. The document also focuses on potential hazards arising from the technology, based on an expert consultation to comprehensively identify possible food safety hazards.

The report devotes an introductory chapter to a description of the technologies used in the development and production of cell-based foods, along with a survey of applicable regulations in about a dozen countries or jurisdictions. The next chapter presents case studies of product development, commercialization and regulation in three countries: Israel, Qatar and Singapore. After a chapter discussing the possible safety hazards that could arise from the technology, the report concludes with a summary of its conclusions and recommendations for a path forward. The conclusions stress the need for application of the appropriate scientific knowledge, including correct terminology, and the need for hazard identification, in order for governments to conduct risk assessments of new products in this field, and the report calls for cooperation among countries to share knowledge and expertise as the field develops.

I’ve only begun to review the report by focusing on the sections dealing with international regulation of cell-based foods. The report summarizes the applicable regulatory frameworks in important jurisdictions like the U.S., Europe, Australia and New Zealand, Japan and other countries, concluding that, in most cases, existing laws and regulations such as those governing “novel foods” would be applicable to the market introduction of cell-based foods in these jurisdictions. I would note, however, that the findings of the report address the state of the industry up to March 1, 2022, and so some of the regulatory descriptions are not fully up to date. In particular, the section on the U.S. framework does not discuss FDA’s voluntary consultation program for human food made from cultured animal cells, under which two products have received “no questions” letters from the FDA in recent months: food products made from cultured chicken cells from UPSIDE Foods (November 2022) and GOOD Meat, Inc. (March 2023) (I plan to discuss this program and these approvals in an upcoming blog post). Strangely, the report also does not address the fact that several related products have been reviewed by FDA under their GRAS Notice program, including the GRAS Notice submitted by Impossible Foods for the soy leghemoglobin from genetically modified microorganisms that it uses to provide texture to its plant-based meat products, which received FDA’s “no questions” letter in July 2018.

I hope to be able to review the FAO report in more detail in the coming weeks, and to post additional comments here on the blog.

Recently-Approved MCANs

From time to time, I’ve posted analyses of recent Microbial Commercial Activity Notices (MCANs) reviewed and received by the U.S. Environmental Protection Agency (EPA) under its biotechnology regulations (40 CFR Part 725). Since the 2016 enactment of the Lautenberg Amendments to the law on which these regulations are based, the Toxic Substances Control Act, or TSCA, EPA has changed the way approved MCANs are posted on the agency’s website. Some of these changes are for the better – approvals are posted much more quickly after the approval date, as opposed to the old system where approval lists were often many months out of date. However, the new format of the approval listings has made it a bit harder to learn much of any value regarding the microorganisms covered by the MCANs and their company applicants.

One page on the EPA website is an “MCAN Table”, which is dedicated to the biotechnology program and which lists in one place all the MCANs approved since the June 2016 amendments, with 200 entries as of April 10, 2023. However, this page does not show any information other than the submission and approval dates, and in particular does not identify the applicant (where that is not confidential) or provide the generic (non-confidential) names of the organisms. A more informative page is the “Chemicals Determined Not Likely to Present an Unreasonable Risk” page, which includes biotechnology submissions along with all other submissions for chemical substances under Section 5 of TSCA, and includes 547 entries as of April 10 submitted since June 2016. This page is searchable, and by searching for the MCAN prefix “J”, it’s possible to develop a list of MCANs approved since 2016. Although this list does not identify the applicants, working from this listing is advantageous because each entry includes the generic name of the microorganism with a link to EPA’s decision document for each MCAN. Although the decision documents rarely contain any information specific to the organism that is the subject of the MCAN, this table provides more information than the “MCAN Table” mentioned above.

The latter table allows the following to be said regarding approved MCANs submitted during Fiscal Years 2021, 2022 and 2023 to date (i.e. submitted since October 1, 2020). As of April 10, 2023, of those MCANs submitted in this time period, 50 were approved (note that when consolidated MCANs are filed, each of the strains is assigned its own MCAN number, so these 50 assigned MCAN numbers correspond to about 24 discrete submissions). Of the fifty, 23 were identified in the generic organism name as covering genetically modified Saccharomyces cerevisiae, while the other 27 were for other microbial species or were for MCANs for which the identity of the species was claimed as confidential (although several of these were for “modified yeast” strains, some of which may also be S. cerevisiae). The listings include a “generic use” for the organisms, and among the uses cited were biofuel production, production of chemicals, enzymes or other proteins, nucleic acids, or agricultural products. (For full disclosure, I should add that I prepared or assisted in the preparation of 10 of these 24 submissions on behalf of several clients).

There isn’t much more that can be said about these MCANs without obtaining the nonconfidential copies of the filings from EPA’s public information offices. However it is interesting that these figures show that EPA is receiving and approving approximately 20 or more MCANs per year, which is perhaps a bit below the historical peak, but is still a decent size workload. It’s also interesting that many of the S. cerevisiae MCANs specifically reference the production of biofuels, at a time when industry interests are shifting towards production of bio-based chemicals with less emphasis on products like biofuels that generally have lower profit margins.

USDA Issues Draft Guidance for Microorganism Permit Applications

On March 23, 2023, the U.S. Department of Agriculture’s (USDA) Animal and Plant Health Inspection Service (APHIS) announced that it had issued a draft guidance document describing information requirements and procedures applicants should follow when submitting permit applications for microorganisms developed using genetic engineering.

USDA’s biotechnology regulations under 7 CFR Part 340, recently updated in 2020, are the rules under which the agency has regulated the interstate movement and environmental release of organisms that may pose a plant pest risk. According to the APHIS website, the 2020 revisions enable the Agency “to regulate organisms developed using genetic engineering for plant pest risk with greater precision and [to] reduce regulatory burden for developers of organisms that are unlikely to pose plant pest risks”. This rule has primarily been used to cover the field testing and outdoor growth of GMO (transgenic) plants, but the regulation also covers certain microorganisms that have been genetically modified and which might pose a risk as a plant pest. Of the 1,540 entries in APHIS’s database of permit applications and notifications it has received under this regulation, 75 are identified as “bacteria” (of various species) and 11 for “fungi” (as well as 66 for “viruses”).

The draft Guide for Submitting Permit Applications for Microorganisms Developed using Genetic Engineering Under 7 CFR part 340 is available for downloading on the APHIS Biotechnology Regulatory Services Guidance webpage. Interested parties may view and submit comments at https://www.regulations.gov/docket/APHIS-2023-0030/document. The Agency will consider all comments submitted through May 22, 2023, after which the Agency will finalize the Guide.

The guidance document consists of introductory sections describing the Part 340 Rule and the organisms it might cover. After describing the process by which permit applications are to be submitted, the Guide describes the specific information needed for applications either for interstate movement or for environmental release (e.g. field testing or other experimentation) of modified microorganisms that might be subject to the rule. In either case, the applicant must submit detailed information on the organism, its taxonomy, how it was constructed, and its genotype and expected phenotype. The guidance for environmental use is more detailed, and asks applicants to provide information on the site of the proposed field test, the planned procedures to confine the organism to the test site, procedures for detection and monitoring of the organism and its possible spread beyond the test site, and procedures for devitalization of the organism at the conclusion of the trial. For both types of permit applications, at least one Standard Operating Procedure must be submitted that describes procedures for how the organism will be contained during movement between sites, and how it would be confined during any field release.

Although oversight over modified agricultural microorganisms has only been a minor application of the Part 340 regulation since its inception, it is important because it could potentially cover the types of microorganisms that are being developed for various agricultural purposes, including potential biostimulants, organisms promoting improved nutrient uptake, plant pest biocontrol agents, and others, at a time when many companies and research labs are indeed exploring uses of microorganisms for such purposes. In addition, certain microbes regulated under this rule could also be subject to review or regulation by the Environmental Protection Agency under the pesticide law FIFRA or the chemical law TSCA.

Working with Partners and Customers on Industrial Biotechnology Regulatory Strategies: Part 4

This is the fourth and final entry of a series of posts in which I’ve presented an expanded version of a presentation I made in May 2022 at the AIChE 5th Commercializing Industrial Biotechnology conference in San Diego, discussing strategies for planning and implementing regulatory submissions for industrial biotechnology projects involving a partnership with another party. In the first entry, I summarized the different types of relationships that might govern industrial biotechnology commercialization efforts, and presented a summary of the types of information typically needed in biotechnology regulatory submissions. In the second post, I discussed the issues and challenges that might be faced in preparing regulatory dossiers for these different types of commercial partnerships. The third post addressed issues that might arise when the commercial project will take place in a foreign country, under the jurisdiction of a possibly unfamiliar regulatory agency. Today’s post will complete the series with some recommendations for approaching regulatory submissions for projects involving commercial partners.

Recommendations

Although these various scenarios offer differing challenges, they nevertheless share enough similarities so that I can offer some general recommendations for planning regulatory submissions for such collaborative projects.

First is the advice I give to any company contemplating the need for regulatory approvals, which is to plan ahead. It is wise to begin internal planning at least 9-12 months before intended start date, where possible, perhaps longer if the collaboration will be international. Most biotechnology regulations specify agency review periods of at least 90 days, although some can be quite a bit longer, and this of course varies from country to country. This advice applies not only to internal planning but also to your communications with the partner regarding the likely regulatory roadmap. It is necessary to involve your third party partners as early as possible in the process, and to set clear expectations from the outset.

Along these lines, it is important to clearly establish the responsibilities of the respective parties in developing the information and data needed in the regulatory process. In some cases this can be addressed in the partnership agreement between the parties, in which the roles and responsibilities of the partners will often be specified. But you need to make clear to the partner as early as possible what your expectations or needs may be for the information and other assistance you’ll need from them,

Communications can be difficult where the third party is a customer or licensee: be sure the third party understands the need and value of the regulatory process. Some partners for industrial biotech projects may operate in industries or countries where there is little or no regulation, or in most cases the partners will not be familiar with the way biotechnology processes are regulated. You should be sure they understand and accept the necessity and the legitimacy of the regulatory process, and are committed to helping you achieve success. Finally, as mentioned above, it will often be necessary to explain agency policies towards company confidential information, to ensure your partner that their information will be protected.

This is the final installment in this 4-post report. To obtain a PDF copy of the entire report, in the form of a white paper, please contact David Glass at dglass@dglassassociates.com.

Working with Partners and Customers on Industrial Biotechnology Regulatory Strategies: Part 3

This is the third of a series of posts in which I’m presenting an expanded version of a presentation I made in May 2022 at the AIChE 5th Commercializing Industrial Biotechnology conference in San Diego, discussing strategies for planning and implementing regulatory submissions for industrial biotechnology projects involving a partnership with another party. In the first entry, I summarized the different types of relationships that might govern industrial biotechnology commercialization efforts, and presented a summary of the types of information typically needed in biotechnology regulatory submissions. In the second post, I discussed the issues and challenges that might be faced in preparing regulatory dossiers for these different types of commercial partnerships. Today’s post will briefly address issues that might arise when the commercial project will take place in a country other than your own, and would thus be subject to jurisdiction of a possibly unfamiliar regulatory agency.

Dealing with Foreign Regulatory Agencies

Any of the above relationships may pose additional challenges when the use of the microorganism will take place in another country. Naturally, such uses will be regulated under laws and rules of the country where the activity will take place, and often it will be the entity onsite who will be responsible for the regulatory filing and for obtaining any needed permits or approvals. Even where that is the case, the company that has developed the microorganism will need to provide considerable information to the onsite partner, or in some cases even prepare the entire regulatory dossier on the partner’s behalf. Many of the issues discussed above will come into play, with the added complication that you’d be dealing with regulations and regulatory agencies with which you are likely not that familiar.

The following are some recommendations for dealing with a situation where your partnered project is regulated in another country.

First, obtain an early understanding of the regulatory definitions and requirements in the country where the use will take place. Regulatory regimes differ around the world, and organisms regulated in one country may be exempt in another.
You clearly can’t do this alone, and assistance from your partner is essential. In most cases, the application will need to be submitted in the name of the local facility even if you as the strain developer prepares most or all of the content of the dossier.
It is likely that submissions must be filed in the national language of the host country, and so there may be considerable information that will need translation. However, I have found in at least one European jurisdiction that the scientific content of the application was able to be submitted in English even though most other information in the application needed to be in the local language. That is unlikely to be the case in countries like Japan or China, and so you may need to rely on your partner or other local resources in getting documents translated.
It could be worth considering whether a local attorney or regulatory consultant is needed. This would be less likely if your partner is a functioning biotechnology company and is familiar with national biotech laws and regulations. But if your partner is a customer operating in a different industry (e.g. a cement producer from whom you’ll be taking CO₂ from their off-gas), they will likely not have much if any familiarity with the applicable regulations, and so you may need additional professional assistance.

I’ve had reasonable success in coordinating regulatory submissions outside the U.S. in those situations where my client had a good relationship and good lines of communication with the overseas partner. However, there’s no doubt that working with a partner outside your home country adds additional challenges to be managed in developing and submitting a regulatory dossier.

The final installment of this report will appear in an additional blog post within the next few days. To obtain a PDF copy of the entire report, in the form of a white paper, please contact David Glass at dglass@dglassassociates.com. 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-five 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. In addition to his work as a consultant assisting industrial biotechnology companies prepare for and comply with government regulations, he has served as Director of Regulatory Affairs for Joule Unlimited Technologies and Vice President of Government and Regulatory Affairs for BioTechnica International. Dr. Glass has extensive experience with the biotechnology regulations of the U.S. EPA and other agencies, and has coordinated or assisted in the preparation and submission of 18 successful Microbial Commercial Activity Notices and several other biotechnology submissions in the U.S. and other countries. Dr. Glass holds a B.S. in Biological Sciences from Cornell University and a Ph.D. in Biochemical Sciences from Princeton University.

Working with Partners and Customers on Industrial Biotechnology Regulatory Strategies: Part 2

This is the second of a series of posts in which I’m presenting an expanded version of a presentation I made in May 2022 at the AIChE 5th Commercializing Industrial Biotechnology conference in San Diego, discussing strategies for planning and implementing regulatory submissions for industrial biotechnology projects involving a partnership with another party. In the first entry I summarized the different types of relationships that might govern industrial biotechnology commercialization efforts, and presented a summary of the types of information typically needed in biotechnology regulatory submissions. In today’s post, I discuss the issues and challenges that might be faced in preparing regulatory dossiers for these different types of commercial partnerships.

Working with Partners on Regulatory Submissions

Preparing an industrial biotechnology regulatory submission such as an MCAN for the U.S. EPA can be a complicated undertaking, even when the entire commercial process is controlled by a single company. Information and input must be obtained from several different departments or individuals within the company, including the molecular biologists who have created and tested the strain(s), the engineers and fermentation scientists who are responsible for scale-up, production and downstream processing, company safety officers who would be developing relevant SOPs, with input possibly also needed from patent attorneys, marketing staff, and others in senior management. Compiling the regulatory dossier becomes even more challenging for projects involving a partner, when significant portions of the required information must be obtained from the partner in a timely manner. I’ll discuss these challenges as they apply to the different components of the regulatory dossier.

Obtaining Biological Information

As mentioned above, regulatory dossiers will need complete, detailed descriptions of the construction and characterization of the microorganism. The level of detail is comparable to what is typical for a scientific publication or a patent application and will usually require inclusion of construction flowcharts and plasmid maps showing intermediate strains and constructs, and sequence information for all introduced genes and their protein products. In my experience, it can sometimes be challenging to compile all the necessary information even when the strain was developed in-house and all the data is in the hands of company scientific staff, and so it is important to include all the appropriate staff members in the dossier drafting effort.

The task gets more complicated if the strains have been in-licensed or obtained from a partner or other third party who was the strain developer. It is first necessary to clearly explain to your partner the level of detail that will be needed by the regulatory agency, and to discuss with the partner how best to obtain it. The strain developer likely possesses the information you need, but it may be in the form of written progress reports or patent applications, and in some cases it could be written in a different language and require translations. Depending on the nature of the relationship, there may be extreme sensitivity regarding the confidentiality of the strain construction information, and in some cases the strain developer may be reluctant to share such information even with you as their partner or licensee. You may need to assure your partner that regulatory agencies in most countries are diligent about protecting the confidential information of submitters, and that any information the partner provides to you will be identified as confidential and protected by the agency.

In my experience, preparing a regulatory dossier works best when iterative drafts can be traded among the relevant team members, but this may not always be easy when working with a partner. In particular, there can be significant challenges when the strains in question have been in-licensed from another company or an academic institution. I’ve encountered situations where the strain developer has been very reluctant to share the needed information with my client and with me. In one case, I had to sign an NDA with the institution that licensed the strains to my client. I’ve also had situations where the strain developer was located in a different country, and in those cases, in addition to concerns about the confidentiality of the biological information, we occasionally encountered translation problems when key documents were available only in a language other than English.

The overriding recommendation is for the company preparing the submission to ensure that lines of communication with the strain developer are open, and that your expectations are made clear. You can involve the strain developer in the preparation of the dossier to the extent desirable, and include their team members when developing drafts of the submission, but above all it will be necessary to ensure the partner that their confidential information is absolutely required in the submission but that once included, it will be protected from disclosure to the fullest extent allowed under the relevant laws and regulations.

Risk Assessment; Health and Environmental Effects

Conducting a rigorous risk assessment of potential adverse health or environmental effects of the strain that is the subject of the dossier is not necessarily required for U.S. MCAN submissions, but it may be required under many foreign regulations, particularly those based on the principles of the Cartagena Protocol, which in many instances places the burden for an initial risk assessment on the submitter. Since in many cases the needed assessment can be carried out through a literature search and review, this is the category of information for which assistance from a partner would be less likely to be needed. One exception would be the need to obtain full nucleotide and protein sequences for the heterologous genes and gene products for use in querying online databases of toxic or allergenic sequences. This is information you would need if you have licensed the production strain from a strain developer as discussed above, and it would also come into play to complete the risk assessment.

I have not encountered any significant problems working with clients and their partners in performing risk assessments. Firstly, a rigorous risk assessment may not always be necessary, particularly when the production organism is a strain of a common industrial species such as S. cerevisiae or E. coli, or in other scenarios where one can cite prior regulatory documents attesting to the safety of the species. Second, much of the needed information will be in the public domain in the scientific literature, although as mentioned above, it would be necessary to obtain DNA and protein sequences to query against online databases, and if this information is in the hands of a strain developer or other third party, that could delay or hinder the completion of the risk assessment. However, it is worth noting that in many jurisdictions, particularly under the U.S. EPA regulations, applicants are required to bring to the agency’s attention any information known to it that pertains to the potential health or safety risks of the microorganism or the process, and to the extent your partner possesses any such information, it might need to be included in your submission.

Obtaining Process Information

As noted above, regulatory dossiers will usually require very detailed descriptions of the fermentation facility and its containment controls and features. When the production facility is under the control of the company preparing the regulatory submission, this information should be readily available, although applicants should be sure that all the right people within the company are involved in dossier preparation, to facilitate preparation of the needed information. This would mean including fermentation scientists, engineers, safety officers and other production plant operational staff, as may be needed to obtain critical information for the regulatory submission.

Challenges may arise when the production facility is not under the direct control of the regulatory applicant, and this could encompass several different scenarios. The most common would be where the applicant is using a contract manufacturing organization (CMO) for toll manufacturing, but it could also arise when commercial use of the microorganism will take place at the facilities of a strategic partner, a licensee, or a customer. The nature of the relationship between the applicant and the third party will dictate how easy or difficult it may be to obtain the needed information.

It would first be necessary to clearly convey to the third party exactly what information will be needed for the regulatory dossier. Although this varies from country to country, in most cases the regulatory agency will need to see a detailed description of the fermentation process, the location, layout and operation of the production facility, a process flow diagram at some level of detail, and the procedures and controls that are in place to minimize escape of the organism from containment. As is the case with biological information from a strain developer, the third party in this scenario may well have concerns over disclosing too much information about their facilities and processes, although this may differ depending on the nature of the relationship. It will be important to stress for the partner that in most cases, process or manufacturing information can be claimed as confidential in regulatory filings.

In one scenario, if the third party is a CMO or contract research organization (CRO), particularly those located in the United States, they may be very familiar with the applicable regulatory requirements and in fact may have assisted other clients in preparing regulatory dossiers. And in some cases, especially for CMOs associated with or managed by academic or other non-profit institutions, much of the needed information about their facilities may be public knowledge. So this type of third party should be the most cooperative in providing the information applicants need for regulatory submission. However, I have encountered situations where CMOs have not initially been forthcoming with the needed information, likely out of concerns of not wanting to share too much proprietary information with its clients, so you would need to ensure you’re talking to the right people at the CMO and that they understand what information is needed for the dossier.

If the third party is a strategic partner, a joint venturer, or has some other close business relationship with the applicant, there should be existing lines of communication (and likely an existing NDA) that will facilitate the needed information exchange. Also in this scenario, the third party would share the commercial goals of the project and thus have some “skin in the game” and be invested in the success of the regulatory submission. Even in this situation, it would be necessary to be sure that the needs of the regulatory agency are clearly conveyed to the partner, and to ensure that you are working with those staff from the partner company best equipped to provide the needed information.

The most challenging third party relationship is likely the situation where the process is one that requires an industrial feedstock like woody biomass, carbon dioxide or methane, and where the process will be co-located at an existing industrial facility where the applicant’s customer already maintains a commercial operation from which that feedstock is generated. Here, the relationship between the regulatory applicant and the third party may be more arms-length, and may also be at an early stage, that is, before a long-term customer-client relationship is established. So the third party may be somewhat reluctant to share much information about their facility. But this type of relationship poses another challenge, because the applicant would likely be installing its process at a functioning industrial site that is being used for a completely different purpose, and which may not be as well-equipped to handle biological production processes as would a dedicated facility like a CMO. So, not only might you encounter problems obtaining the needed information from the third party, in some cases the information may not exist, or the third party may not be in a position to provide it.

I’ve encountered this last scenario with one client in particular, where my client was planning to use their proprietary microorganism in a relatively small pilot reactor being installed at two existing facilities of a customer (in different countries). Although my client could of course describe their own reactor, its design and operation, it was challenging obtaining sufficient information about the customer’s facility, site layout, staffing and other required information. In fact, one situation was in a non-English speaking country, adding to the difficulties. In cases like these, it is necessary for the regulatory team to coordinate and work with the team at the company that is responsible for maintaining the relationship with the customer. This will ensure that lines of communication remain open, and more importantly that they are handled in a manner that will not jeopardize the company’s overall relationship with the customer.

The final type of relationship to be considered is where you, as the technology developer, may have licensed the technology to a third party who would practice the technology independently in return for financial or other compensation. In some scenarios, this may pose no problem at all: for example, under the U.S. EPA’s biotechnology regulations under TSCA, if the specific strain of the organism is the subject of an approved Microbial Commercial Activity Notice, the strain can be used at any facility in the U.S. by any company or institution. But if your licensee is in a country where regulatory approval has not yet been achieved, you will have to collaborate with the licensee to gain such approval. Most likely the application will need to be filed in the name of the entity who will actually be practicing the technology in the country, so you’ll find yourself in the position of needing to provide much of the needed information to the partner. In fact, although the application will be filed in the licensee’s name and will likely include a description of their facilities and processes, you as the technology developer might wind up preparing most of the application or dossier. In any event, like in all the other scenarios discussed here, frequent and open communication with the licensee will be necessary (it would be a good idea to anticipate all this, by having the license agreement spell out each party’s roles in seeking regulatory approvals).

The remainder of this report will appear in additional blog posts over the next few days. Please revisit the blog to access these later installments. To obtain a PDF copy of the entire report, in the form of a white paper, please contact David Glass at dglass@dglassassociates.com.

Working with Partners and Customers on Industrial Biotechnology Regulatory Strategies: Part 1

This is the first of a series of posts in which I’ll present an expanded version of a presentation I made in May 2022 at the AIChE 5th Commercializing Industrial Biotechnology conference in San Diego. The genesis for the talk was my realization that much of my work in helping clients prepare U.S. and foreign regulatory submissions, including Microbial Commercial Activity Notices (MCANs) under U.S. Environmental Protection Agency regulations, involved projects for which my clients had partners of various kinds, and where we needed to obtain information or other cooperation from such partners. Partnering is such an important component of the business strategy of any technology developer, particularly in many sectors of biotechnology, that I realized that the problems I was helping my clients overcome were commonly encountered by many companies under different regulatory regimes. So I thought that a presentation discussing the different challenges that may arise under partnering arrangements of different kinds would have some universal appeal.

The discussion that follows will largely focus on industrial biotechnology projects (e.g., using engineered or enhanced microorganisms to produce chemicals, fuels or other specialty products), for which the company spearheading the project is working with one or more third parties. Although focused on industrial biotech projects and the procedural and data requirements that arise in gaining regulatory approvals, much of this discussion could well be applicable to regulatory procedures for other types of products, including food ingredients, pharmaceuticals or other biotechnology products.

Types of Third Party Partnering Relationships

The typical scenario where an industrial biotechnology process requires regulatory approval is where, after some years of laboratory research followed by development and testing in pilot facilities, a company is ready to begin commercial production of a microbially-produced product, whether at a full-scale commercial facility or a smaller demonstration plant. There are several different types of partnering relationships that could arise for such projects, which might involve the following categories of third party partners.

Licensors: In one scenario, another company or an academic research lab may have been the original developer of the microbial production strain for the process that is the subject of the regulatory application. These types of arrangements are typically arms-length, and the licensor will usually have little or no involvement in the commercial process, but the licensee spearheading the regulatory process may need the licensor’s cooperation in several ways to gain regulatory approval.

Contract Manufacturers or Contract Research Organizations: Many small to midsize biotechnology companies do not have the facilities to manufacture products at large scale, and in fact may have trouble raising the capital needed to build such production plants until the product’s market potential is demonstrated. It is therefore common for small technology developers to contract with organizations having the needed fermentation capacity to begin commercialization of the desired product. These third parties would maintain their own capabilities in fermentation and downstream processing but will usually possess no unique knowledge regarding the production microorganisms. The third party would have access to information about the manufacturing facility and the planned process that would be needed for regulatory submissions.

Strategic Partners or Joint Venturers: A small technology developer might have developed a relationship with a larger company, through a research partnership or a commercial joint venture, in which initial commercialization of the product would take place at the partner’s facilities. This scenario is similar to the CMO/CRO scenario where the partner would control important information about the facility and procedures, except that one would expect the relationship of the parties to be closer, in that the proposed project would be taking place in the context of a broader strategic partnership between the companies, thus facilitating the needed communications.

Licensees: In other scenarios, a technology developer may be able to hand off its entire production process, including the microbial strain, preferred fermentation parameters and other know-how, to a third party that would carry out the process and commercialize the product as an arms-length licensee, in exchange for royalties or other financial consideration. Perhaps the most common way in which this would occur would be licensing a third party in another country to access international markets which the technology developer cannot itself address. This type of relationship poses unique challenges, because in many cases, particularly in international transactions, it is the licensee that may have the burden of obtaining regulatory approval for the project, thus potentially complicating the process of information sharing, and reversing the roles in which your company and the partner would find itself.

Customers/Clients: Finally, the nature of certain industrial biotechnology processes creates an additional partnering scenario. For those microbial processes requiring a unique feedstock, such as woody biomass or a waste gas such as CO₂ or methane, the technology developer would be seeking to co-locate its manufacturing facilities at the sites of customers or clients who can provide a dedicated source of the desired feedstock. In this scenario, the technology developer might be building its own stand-alone process at the partner’s site (whether in a permanent or mobile unit), and although the developer would possess the needed knowledge about the organism and the process, the client may be needed to provide other information about the site and resources available at the site; and in some cases it might be the customer that would handle the regulatory submission, particularly in international transactions.

Key Components of regulatory dossiers

Elsewhere in the blog, I have described regulatory regimes that are applicable to industrial biotechnology projects, including the U.S. FDA GRAS Notice program, biotechnology regulations of the U.S. Environmental Protection Agency that apply to uses of certain modified microorganisms in the manufacture of chemicals and certain other products, and biotechnology regulatory regimes elsewhere in the world. Most of my work involves helping companies comply with the U.S. EPA regulations but I’ve also assisted with applications to other agencies in the U.S. and internationally. In general, the data requirements and nature of the agency review would be similar from regulation to regulation, and from country to country (naturally with some variation). The following are the likely components of most regulatory submissions for industrial processes, modeled on the typical contents of Microbial Commercial Activity Notices under the EPA TSCA regulations.

Detailed description of the construction of the microorganism. Most regulatory agencies will require a complete, detailed description of how the organism was constructed, with details on all intermediate strains and methodologies used, and submission of nucleotide and amino acid sequence information for the modified traits. This will often also require evidence confirming the taxonomy of the starting species.
Biological characterization of the microorganism. Although the need here might vary depending on the jurisdiction, it will often be necessary to show provide some data to show the phenotype of the modified microorganism (i.e. to demonstrate that it can fulfil the purpose for which it was engineered), and to compare its growth or performance to a nonmodified strain.
Information on potential health or environmental risks of the proposed use. Most regulatory jurisdictions will require submitters to perform some form of risk assessment of the microorganism and the proposed use. This can often be carried out by a literature review to determine what is known about the potential pathogenicity, infectivity or environmental effects of the species, or the potential for toxicity or allergenicity of any introduced gene products in the subject microorganism. In the regulation of microbial products for industrial use, applicants may not be required to carry out any specific toxicology or similar testing, as would be common for pharmaceuticals, pesticides, etc.
Detailed description of the fermentation process. It will usually be required to provide a detailed description of how the organism will be scaled up (e.g. from seed cultures) and how fermentations will be carried out, including media composition and growth conditions (e.g. pH, temperature, etc.). In most jurisdictions, it would be important to describe and validate the methods by which the microorganism will be inactivated at the end of the process. Some information may be required on downstream processing, particularly any stages of the process where live organisms may still be present.
Detailed description of the production facility, including containment controls, worker protection, relevant SOPs. Finally, the procedures and controls for containment of the organism to the production facility must be described. These would include procedures for biological containment, physical features of the process such as filters or scrubbers on fermenter vents, provisions for worker protection (such as protective clothing), and standard operating procedures for operations associated with the fermentation or for emergency spill clean-up.

The remainder of this report will appear in additional blog posts over the next few days. Please revisit the blog to access these later installments. To obtain a PDF copy of the entire report, in the form of a white paper, please contact David Glass at dglass@dglassassociates.com.

The Blog Renamed

I’m planning to be more active this year in posting on the blog, after a few years of only sporadic activity. So I’ve also taken this opportunity to rename the blog to reflect what will be its broader focus.

I began the blog way back in 2010, as I was beginning to explore the need for my expertise in what was then the growing field of biofuels: the production of renewable transportation fuels using biological methods and technologies. Given my background in molecular biology and biotechnology, and the particular experience I have had with some of the U.S. regulations that were beginning to apply to certain biofuel production technologies, I directed the blog’s early focus on those uses of genetic engineering and other advanced biotechnology techniques to the production of fuels, hence the blog’s original name “Advanced Biotechnology for Biofuels“. Many of the earliest posts on the blog highlighted the companies that were (at that time) using such techniques either to improve plant-based feedstocks for fuel production or to develop microbial-based strategies for the manufacture of ethanol, diesel and other transportation fuels.

Over the years, as my circumstances allowed, I continued to post, mostly sticking pretty close to my main area of expertise with regulatory matters such as the U.S. EPA’s biotechnology regulations under TSCA, but as the industry itself matured and changed to shift its focus away from fuels and more towards higher-margin products such as industrial chemicals and specialty ingredients such as flavors, cosmetics and food additives, my client base and the blog widened their focus as well. Most of the more exciting new companies and technologies in the space known as “industrial biotechnology” are developing these types of products, and the balance of my work shifted towards helping bio-baed chemical companies achieve regulatory approvals for their products and technologies. Over time, the contents of the blog began to reflect this as well, with posts touching on topics such as animal and human food ingredients, alternative (cultivated or plant-based) meats, and other specialty products.

As 2023 has begun, I expect to again be able to devote the time to more frequent, and more varied posts on the blog. In doing so, I felt that a change in the blog’s name was long overdue, to make clear that its focus was broader than simply biofuels or renewable fuels. Hence the new name “Bio-Based Chemicals and Fuels: Business, Policy and Regulation“. I’ll continue to comment on U.S. and industrial biotechnology regulatory matters, but I also hope to post on other topics relating to the innovative uses of biology for the development of beneficial products in the so-called bio-based economy, including technologies that many expect will lead to reductions in fossil fuel use as the world struggles to address the threat of climate change.

D. Glass Associates, Inc. is a consulting company specializing in government and regulatory support for renewable fuels and industrial biotechnology. David Glass, Ph.D. is a veteran of over thirty-five 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. He has extensive experience with the biotechnology regulations of the U.S. EPA and other agencies, and has coordinated or assisted in the preparation and submission of 18 successful Microbial Commercial Activity Notices and several other biotechnology submissions in the U.S. and other countries. Dr. Glass holds a B.S. in Biological Sciences from Cornell University and a Ph.D. in Biochemical Sciences from Princeton University.

Lots of recent action on regulatory agency public comment periods

The early weeks of the new year are seeing a lot of activity from several U.S. government agencies having oversight over industrial biotechnology, food biotechnology and renewable fuels. Several public comment periods are now underway on proposed regulations, agency initiatives, or requests for information, some of which address potentially important issues for certain applications of advanced biotechnology. These activities include the following:

Biotechnology Coordinated Framework. In what might potentially be a broad, far-reaching inquiry, the Office of Science and Technology Policy (OSTP) announced in December 2022 a Request for Information entitled “Identifying Ambiguities, Gaps, Inefficiencies, and Uncertainties in the Coordinated Framework for the Regulation of Biotechnology”. First issued in 1986 and updated in 2017, the “Coordinated Framework” represents the U.S. government’s approach to regulating the diverse products that can be developed using biotechnology, and includes regulations administered by the Food and Drug Administration (FDA), the Environmental Protection Agency (EPA) and the Department of Agriculture (USDA). In a September 2022 Executive Order issued by President Biden, OSTP has been charged with soliciting information from stakeholders on ambiguities and gaps in the framework that might affect the efficient development and regulatory approval for biotech products. A public comment period is open until February 3, 2023. (Another RFI was also issued as a result of this Executive Order, “Request for Information: National Biotechnology and Biomanufacturing Initiative”, but its comment period is expiring on January 20, 2023). The RFI listed 7 specific questions on which comment is solicited, the most important of which are the identification of supposed gaps or ambiguities in the Framework and consideration of their impact, including economic impact, on biotechnology product development.

Animal Feed Ingredients. It is the FDA Center for Veterinary Medicine (CVM) that has regulatory responsibility for animal foods and food ingredients, but as readers of this blog know, FDA CVM also participates in a parallel program for review of feed ingredients maintained by the Association of American Feed Control Officials (AAFCO). The AAFCO program provides an alternative path for review and approval of novel feed ingredients, but CVM staff has conducted the technical reviews of products submitted to AAFCO under this program. In a December 2022 announcement, FDA announced that it will be holding a virtual public hearing on February 9, 2023, to discuss FDA’s role in the AAFCO feed ingredient process. The agency will also entertain public comments on this topic through March 9, 2023. The agency listed the following issues on which comment is solicited:

What steps can FDA take to improve stakeholder understanding of FDA’s engagement with AAFCO’s feed ingredient definition process and better communicate this information with the public?
What changes to FDA’s role in AAFCO’s feed ingredient definition process would be helpful to stakeholders and why?
If FDA made a list of AAFCO feed ingredient definition requests publicly available, where would stakeholders prefer to find such a list and what information would stakeholders like to see with such a list?
What do stakeholders view as successful or valuable in FDA’s continued participation as the scientific reviewers for new AAFCO feed ingredient definitions?

Renewable Fuel Standard. On December 1, 2022, EPA announced a proposed rule to establish the required Renewable Fuel Standard (RFS) volumes and percentage standards for 2023, 2024, and 2025. The proposed rule also included a series of modifications to strengthen and expand the RFS program. The RFS is the federal government’s major program promoting the use of renewable and low-carbon fuels for automotive and aviation use, by establishing yearly mandated volumes for the amounts of such fuels to be sold in the U.S. A public hearing on the rule was held on January 10-11, 2023, but public comments will be entertained until February 10, 2023.

I don’t expect that anything significant will arise from the review of the Coordinated Framework. The previous review of the Framework that took place in the Obama Administration from 2016-2017 resulted only in some clarifications of agency jurisdictions, and (at least to this longtime observer of the government’s biotech policies) did not break any new ground or result in any new or relaxed regulations (it is not clear to me whether the USDA’s 2020 revised biotechnology rule at 7 CFR 340, the so-called SECURE Rule, which was years in the making, could be directly attributed to the 2017 updating of the Framework).

However, there are certainly some areas of potential overlap which are worth comment. One issue of longstanding concern is the possibility that genetically modified microbial soil inoculant products could be subject both to the USDA biotechnology rule and EPA regulations under the Toxic Substances Control Act. Another topic has to do with the regulation of certain animal feed ingredients that are, or include, inactivated microbial biomass arising from industrial fermentations; a topic that has long been of concern to me (as described in earlier blog posts), and where the cooperation between FDA CVM and AAFCO has contributed to long review times and inefficient reviews of potential products. Another area that may potentially draw some public comment is the emerging oversight regime for cell-based or plant-based meat products, also a topic on which I’ve previously commented in this blog. It’s worth noting that the first successful approval was achieved in November 2022 under FDA’s Pre-Market Consultation program for review of foods made from cultured animal cells.

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-five 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 links to some of Dr. Glass’s prior presentations on biofuels and biotechnology regulation, are available 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.