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 firstname.lastname@example.org.
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.