Discussing how advanced biotechnology is being used to improve the production of bio-based chemicals, renewable fuels and other industrial biotech products
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.
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.
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.
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.
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.
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 environmentalrisks 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 atdglass@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.
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.
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.
Today’s post continues a series of analyses of recent submissions to the U.S. Environmental Protection Agency for outdoor field tests of genetically modified microorganisms under the TERA (TSCA Environmental Release Application) provisions of the Agency’s biotechnology regulations under the Toxic Substances Control Act (TSCA). Today’s entry will describe two TERAs for research use of modified algae strains in open-ponds, as part of research programs ultimately aimed at developing commercial processes for production of fuels or high value chemicals.
As previously described, EPA’s TERA regulations were created to provide Agency overview over proposed outdoor experimentation using genetically modified microorganisms, within industrial sectors not regulated by other federal agencies. The requirement for prior EPA approval for such testing allows the Agency to review the potential environmental effects of the proposed activity, but on a shorter (60-day) timeframe compared to requirements for review of proposed commercial activities. The TERA process is well-suited to allow the assessment of the potential risks of proposed environmental uses of modified organisms, while also allowing outdoor uses of modified microorganisms to take place in a stepwise fashion under appropriate monitoring and agency oversight, to enable legitimate scientific issues of environmental risk assessment to be addressed with data from actual controlled small-scale environmental use, thus facilitating subsequent risk assessments for larger-scale uses.
Today’s post discusses two TERAs submitted by Arizona State University on behalf of the Producing Algae for Coproducts and Energy Consortium (PACE). Both applications proposed small-scale experiments entitled “Evaluation of Genetically‐Modified Chlorella sorokiniana in Open Ponds for Production of Biofuel Feedstock and High Value Co‐products”. Chlorella sorokiniana is a unicellular green alga that was described as a well-studied model organism that has long been used in research on photosynthesis and other R&D or industrial applications, including as a food additive. These applications were proposed to take place at the Arizona Center for Algae Technology and Innovation (AzCATI) test bed facility, a 4 acre site in Mesa, Arizona that features laboratories, greenhouses, a number of raceways and miniponds and a photobioreactor array for experimentation with algae technologies.
TERA R-17-0002 was submitted by ASU in May 2016. It proposed the testing of two modified strains of Chlorella sorokiniana. One strain was engineered to express pyrroline‐5‐carboxylate synthase from Vigna aconitifolia (mothbean), which is said to improve stress tolerance, and the other to express AHL‐lactonase from Bacillus sp. strain 240B1, which may play a role in disrupting quorum sensing in algae. Both genes were codon-optimized, and introduced into the recipient algae strain on a plasmid, for expression under the control of native Chlorella regulatory sequences. The goals of the study were to evaluate how well laboratory findings translated to performance in the open environment, and to compare the modified strains to wild type for resistance to environmental factors. The study also aimed to characterize the potential risks and environmental impacts of this open-environment use of modified algae, such as the possibility of dispersal beyond the test site.
TERA R-18-0001 was submitted by ASU in August 2017. It proposed the testing of one modified strain of Chlorella sorokiniana, engineered to express SNRK 2 (SNF related kinase) from the green alga Picochlorum soloecismus, an enzyme involved in sugar metabolism, with the goal of improving photosynthetic efficiency and biomass production. This gene was not codon-optimized, and was also expressed on a plasmid under the control of native Chlorella regulatory sequences. This study had the same goals as the testing proposed in the first TERA. Interestingly, the modified strain described in this application was first tested in a 50 L indoor minipond inside a greenhouse, and was found to have significantly increased carbohydrate accumulation compared to wild type.
These TERAs proposed outdoor experimentation under essentially identical conditions and procedures. Each test was proposed to take place in a total of 6 miniponds, each of which had a working volume of between 800 and 1,000 liters and a surface area of approximately 4.2 m2. The miniponds were set on raised stands and were placed within secondary containment constructed of a wooden frame acting as a berm that was overlaid with an industrial liner. The miniponds were also said to be contained within a 9m x 11m perimeter that was underlined by a mesh‐reinforced, puncture‐resistant, UV‐resistant pond liner. Each test was planned to last for 60 days, during which time samples were to be taken from the miniponds to evaluate biomass accumulation of the modified strains compared to the wild type controls. The experiments also featured monitoring protocols, using water traps at various distances from the miniponds to detect any possible spread from the experimental ponds: sampling was to take place weekly, with more frequent monitoring and other mitigation steps to be taken if any dispersal was detected.
I don’t know if these tests were carried out, but since they were to be conducted by an academic group, results would likely be published eventually. Overall, these TERAs represent a sound, thoughtful approach to proposals for outdoor testing of genetically modified algae, with plans for monitoring that should produce useful data on the environmental impacts of such testing. The submissions themselves were thorough in providing the necessary information for EPA to conduct its risk assessment.
There have been other recent TERAs for outdoor experimentation using modified microalgae, which is hopefully indicative of increased interest in developing industrial uses of geneticaly-improved algae strains, as well as evidence that the tools to improve such strains are becoming more accessible. I hope to discuss these other algae TERAs in future blog posts.
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.
In a recent blog post, I summarized submissions to the U.S. Environmental Protection Agency for outdoor field tests of genetically modified microorganisms under the TERA (TSCA Environmental Release Application) provisions of the Agency’s biotechnology regulations under the Toxic Substances Control Act (TSCA). In today’s post, and the ones that will follow, I’ll briefly describe the most recent TERAs, beginning with those filed with EPA since 2014.
As previously described, the commercial use of modified microorganisms for purposes subject to TSCA jurisdiction might be subject to EPA’s biotechnology regulations under TSCA. Commercial use or importation into the U.S. of certain modified microorganisms (i.e., “new organisms” containing coding nucleic acids from more than one taxonomic genus) for purposes that are within TSCA’s jurisdiction require prior submittal to EPA of a Microbial Commercial Activity Notice (MCAN). Applications potentially subject to TSCA jurisdiction include production of industrial chemicals (including biofuels and certain enzymes), as well as uses of microorganisms for environmental purposes such as bioremediation and non-pesticidal agricultural uses. The latter category might include plant inoculants to promote nitrogen fixation, soil amendments, biofertilizers and plant biostimulants. Although R&D activities are largely exempt from TSCA oversight, the biotechnology regulations require that research involving “new microorganisms” in the open environment (outside a “contained structure”) require EPA review before the research can be conducted, through the filing of a TERA. The TERA process provides an expedited review procedure for small-scale field tests and other outdoor R&D uses of new organisms, with applicants required to submit TERAs at least 60 days in advance of the proposed activity. See my earlier blog post for more background on TERAs, their data requirements, and the review process.
As I reported in the earlier post, there has only been limited experience with TERAs since the biotechnology rule was put into place in 1997. According to EPA’s websites, there have been about 40 TERAs submitted for open environmental use of engineered microorganisms, and all but four of these proposals were approved. I have reviewed the TERAs filed prior to 2014 in previous posts, and in today’s post I will describe three TERAs filed in 2014 and 2015.
TERAs R-15-0001 and R-15-0002 were submitted by Elemental Enzymes Ag and Turf, LLC. According to the company’s website, Elemental Enzyme creates “enzyme, peptide and natural solutions that improve plant health, performance and yield” by applying cross-disciplinary scientific solutions to complex agricultural problems. Their products and processes are “applied through seed treatment, in-furrow soil treatments, foliar applications, tree injection, fertilizer impregnation and fertigation”. These TERAs proposed a series of field tests of a technology in which select beneficial enzymes were expressed on the outermost layer (the exosporium) of spores of Bacillus thuringiensis subsp. Israelensis. The company was developing this technology in the expectation that such spores would be an efficacious way to deliver enzymes directly to crop plants. B. thuringiensis is of course a species well-known for different subspecies that express specific insect toxins, and which have been used as natural biopesticides against lepidopteran and coleopteran pests for many years. However, Elemental Enzymes was not making use of that trait, and in fact their strain of B. thuringiensis subsp. Israelensis was missing the genes needed to encode the insect toxin.
The company created multiple strains of modified B. thuringiensis subsp. Israelensis, each expressing a different plasmid-encoded enzyme. The eight enzymes expressed by these strains were endo-1,4-β-glucanase, β-1,3 glucanase, phytase, chitosanase, protease 2, alkaline phosphatase 4, lipase EstA, and phosphatidylcholine phospholipase. The strains were to be administered either directly to seed or in-furrow, and field tests were planned in 14 states on a variety of crops including corn, squash, tomatoes and cucumber. The purpose of the trials was to determine if the enzymes imparted beneficial growth-promoting properties to any of the crop plants; monitoring of the modified strains was also contemplated.
It is not known in the public record if these tests were carried out and what the result may have been, and there were no follow-up TERAs submitted for these strains. Today, the company is selling or developing a number of products for agriculture, but spore-delivered growth-promoting enzymes do not appear to be among them.
These TERAs are unique in several ways. They are likely the only submissions to a federal agency for a field test involving spores of genetically modified microorganisms. And the proposed experiments were somewhat unusual in the use of a species known for its pesticidal properties for a purpose unrelated to such properties. These TERAs also appear to have been the first for testing of soil inocula since the nitrogen-fixing experiments under TERAs in 1999-2000, which is of interest given the recent increase in commercial activity towards developing improved seed and soil inoculants to improve crop growth and yield.
TERA R-15-0003 was submitted by the National Institute of Standards and Technology (NIST) on April 30, 2015 for a proposed field test of a modified strain of Saccharomyces cerevisiae. This proposal is also one that is unlike any other TERA that has yet been filed with EPA. The purpose of the proposed field test was to test the ability of a modified yeast strain to serve as a “reference material to support first responder training and workflow evaluation for on-site biological assessment technologies”. In response to a 2011 report from the Department of Homeland Security, researchers at NIST were developing a program to train first responders how to deal with “suspicious white powder incidents” that might arise from terrorist activity. The goal of this project was to evaluate whether this modified S. cerevisiae strain could be used “as a qualitative and quantitative reference material for microbial abundance measurements” under conditions mimicking a field response to a white powder incident.
The NIST team modified a wild type S. cerevisiae strain to contain a 438 bp fragment from a heterologous organism, Methanocaldococcusjannaschii, a noncoding sequence selected to have minimal homology to the S. cerevisiae sequences, which could be used to detect the microorganism in PCR assays. In the proposed test under the TERA, cells of the modified strain were to be lyophilized and released to the environment in two ways: either fixed on metal coupons which would be placed at different locations around the test site, or released to the atmosphere in a plume at the site. In the first case, the plan was for the researchers to retrieve the metal coupons and obtain microbial samples using swabs, and the samples would then be quantified using qPCR and viable-cell counting. In the second case, clean metal coupons would be used to collect the microorganisms from the plume, and the coupons used as in the first experiment to obtain microbial samples for qPCR and plate counting.
NIST conducted the test in July 2015 and subsequently filed a report with EPA describing the results. The air plume experiment was not carried out due to unforeseen circumstances, but the first experiment with the metal coupons was conducted. The report concluded “Overall, the use of the yeast was a success. Of the 4 detection sites, only 3 sites reported results. One site did not report results due to technical difficulties at the time of testing. All the reporting sites successfully detected the yeast from the samples collected from coupons with yeast”.
These two proposals from several years ago are indicative of the breadth of R&D activity in exploring the uses of modified microorganisms for beneficial uses in the environment. As noted above, the Elemental Enzyme TERAs can be seen as an early harbinger of renewed commercial interest in developing improved microorganisms for non-pesticidal agricultural purposes, and the NIST proposal is an example of how the techniques of modern biotechnology can be applied in innovative and perhaps unexpected ways.
In the blog post that will follow in a few days, I’ll describe another batch of TERAs, including three successful proposals for open-pond field testing of genetically modified algae.
To conclude, I’ll reiterate my earlier comments that the TERA process is well-suited to allow the assessment of the potential risks of proposed environmental uses of modified organisms. The TERA process allows outdoor uses of modified microorganisms to take place in a stepwise fashion under appropriate monitoring and agency oversight, to enable legitimate scientific issues of environmental risk assessment to be addressed with data from actual controlled small-scale environmental use, thus facilitating subsequent risk assessments for larger-scale uses.
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.
It was recently reported in Biofuels Digest that the European Commission has published an online consultation on its roadmap aimed at promoting a strong and sustainable EU algae sector. This online portal is entitled “Consultation – your view on promoting EU algae production,” and can be accessed here. This effort is an “Inception Impact Assessment,” which in general are aimed at informing citizens and stakeholders about the Commission’s plans for certain initiatives, to seek public feedback and participation in future consultation activities. These Assessments are said to be ways in which citizens and stakeholders can provide views on the Commission’s understanding of a given problem and possible solutions and to provide any relevant information that they may have.
The document summarizing the Assessment can be downloaded as a PDF document here, although the site was somewhat balky today (please contact me if you cannot access this document, and I can send the PDF). The inquiry encompasses a broad scope of potential uses both of microalgae and macroalgae (e.g. seaweed), for uses including food, fuel and specialty chemical production, and the document states that “the initiative aims at increasing sustainable production, ensure safe consumption and boost innovative use of algae and algae-based products”. The document states that the Commission is considering at least three options: the first would be “no policy change”, the second would be what are called “targeted activities to support the sustainable growth of the algae sector” and would include measures to improve applicable regulatory frameworks, improving the business environment for algae products, increasing social awareness and also closing knowledge and research gaps. A third option would include all of the activities under the second option but would also include mandated incentives and quotas for algae products. Public input is sought on a wide range of relevant topics, as the first phase of a process that will culminate in the issuance of reports and recommendations by the fourth quarter of 2021.
The Commission opened a 4-week comment period on December 21, 2020, with January 18, 2021 as the deadline for submissions. Comments can be submitted at this site, or from the “Have your say” link at the portal page.
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.
This guidance document is the culmination of a process that EPA first began in 2015. When the Agency issued its biotechnology regulations in 1997, it finalized an earlier-prepared document called “Points to Consider in the Preparation of TSCA Biotechnology Submissions for Microorganisms“, and this document has remained unchanged since that year, and has been used by submitters of Microbial Commercial Activities Notices (MCANs), TSCA Environmental Release Applications (TERAs) and other biotechnology filings under TSCA. Its guidance largely remains relevant, although it was written well before the advent of advanced genetic technologies now in widespread use such as synthetic biology and gene-editing tools, as well as before advances in nucleic acid sequencing technology made it routine to be able to provide detailed sequence information for all the introduced genetic modifications. I believe EPA has for some time been planning a general update of this document, but to my knowledge the “Algae” supplement is the only effort where proposed new guidance has been made available to the public.
The Points to Consider document, while applicable to all biotech submissions under TSCA, was heavily biased towards information needs for applications involving the most common industrially-used heterotrophic microorganisms, primarily including bacteria, yeast and other fungal species. In 2015, EPA first announced its intention to provide a companion document that would provide additional guidance for submissions involving genetically modified algae and cyanobacteria, which, as photosynthetic organisms, were anticipated to be used in ways different from traditional microbial fermentation. Earlier blog posts described the initial public meeting on this topic that EPA held in September 2015 and the follow-up meeting in October 2016. EPA issued a draft algae guidance document in conjunction with the 2016 public meeting, and the present document is an update to the 2016 version, and incorporates the information and feedback EPA received at that open meeting and from the public records docket that was open for comment at that time.
After some introductory sections, the main body of the guidance document is a detailed, comprehensive list of the types of data that EPA would potentially like to see in submissions for uses of algae or cyanobacteria under TSCA. It follows the framework of the 1997 Points to Consider document, in providing lists of the types of data that might be required in EPA submissions, within a series of broad categories. The algae document first asks for information about the recipient microorganism (i.e. the strain that is the starting point for the genetic manipulations) and the genetic changes introduced, information about the potential health and environmental effects (including the environmental fate) of the alga, and information about the proposed use of the modified alga, whether a small-scale field test proposed in a TERA or a manufacturing use proposed in an MCAN. The document provides additional details about information specific for algae or cyanobacteria that would be important for EPA’s risk assessment of proposed use of modified algae in manufacturing, whether in open ponds, enclosed photobioreactors, or heterotrophic fermentation, as well as proposed open pond R&D activities. As with the original Points to Consider document, the algae guidance document provides a comprehensive list of issues to be considered, with the expectation that not every topic identified would be applicable to every submission. In addition, it should be noted that TSCA itself does not impose specific testing requirements on applicants, but only that notices under the Act include all data relevant to health and safety that is known to the applicants.
After brief review of the final document, it appears that EPA made only some minor revisions to the detailed information section as it appeared in the 2016 draft. I found only about 3 or 4 places where the 2020 version included a bullet point for a new topic of information or data not found in the 2016 draft, which were presumably added in response to specific comments from interested parties. This speaks to the thorough job EPA did in creating the original draft, which was so comprehensive in listing potential data needs that there really wasn’t much that needed to be added.
To date, EPA has received very few TSCA submissions for uses of algae or cyanobacteria, some of which I have described in previous blog posts. For example, discussion of MCANs from Joule and Solazyme (now known as TerraVia) posted in 2014, a brief mention of Algenol’s Consolidated MCAN for cyanobacteria posted in 2015, and discussion of the TERA submitted by Sapphire posted in 2013. Presumably this new guidance document will be of value to companies and academic groups planning MCAN or TERA submissions for modified algae or cyanobacteria species in the months and years to come.
D. Glass Associates, Inc. is a consulting company specializing in government and regulatory affairs support for renewable fuels and industrial biotechnology. David Glass, Ph.D. is a veteran of over thirty-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.
Bio-Based Chemicals and Fuels: Business, Policy and Regulation 