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.
Bio-Based Chemicals and Fuels: Business, Policy and Regulation 