FOA_BioInd_MII_final.pdf

FA8650-20-S-5028

Funding Opportunity Announcement (FOA)

FA8650-20-S-5028

Contents Overview Information

Table 1: Anticipated Program Funding ($ Millions)

Full Text Announcement

I. PROGRAM DESCRIPTION

A. STATEMENT OF OBJECTIVE, GOALS, AND NEEDS

B. BACKGROUND

C. PROJECT OVERVIEW

D. TECHNICAL OBJECTIVES

E. KEY ELEMENTS

F. POST-AWARD REQUIREMENTS

II. AWARD INFORMATION

A. AWARD INTENT

B. ANTICIPATED AWARD DATE

C. ANTICIPATED FUNDING FOR THE PROGRAM

D. NUMBER OF AWARDS ANTICIPATED

E. NON-GOVERNMENT TECHNICAL ADVISORS

III. ELIGIBILITY INFORMATION

A. ELIGIBLE OFFERORS

B. COST SHARING OR MATCHING

C. FEDERALLY FUNDED RESEARCH AND DEVELOPMENT CENTERS

D. FEDERAL GOVERNMENT ORGANIZATIONS

E. FOREIGN INTEREST PARTICIPATION GUIDELINES

F. OTHER

IV. APPLICATION AND SUBMISSION INFORMATION

A. OVERVIEW

B. GENERAL INSTRUCTIONS FOR WRITTEN DOCUMENTS

C. FORMAT AND SUBMISSION REQUIREMENTS

V. EVALUATION INFORMATION

A. EVALUATION CRITERIA

B. REVIEW AND SELECTION PROCESS

VI. AWARD ADMINISTRATION INFORMATION

A. Award Notices:

VII. OTHER INFORMATION

VIII. AGENCY CONTACTS

APPENDICES ATTACHED

Table 1: Anticipated Program Funding ($ Millions) Table 2: Award Information – Anticipated Program Funding ($ Millions) Table 3: Concept Paper Format - Table 4: Full Proposal Format - Table 5: Sample Compliance Matrix -

Figure 1. DoD MII Critical Functions Figure 2. Bioindustrial MII Technical Concept- Figure 3. Bioindustrial MII in the U.S. Biotechnology Ecosystem-

Overview Information

NAICS Code: 541715

Federal Agency Name: Air Force Research Laboratory, Materials and Manufacturing Directorate, on behalf of the Office of the Undersecretary of Defense (OUSD) for Research and Engineering (R&E), Office of the Assistant Director for Biotechnology, and the Manufacturing Technology (ManTech) Program.

Program Name: DoD Manufacturing Innovation Institutes (MIIs)

Funding Opportunity Announcement (FOA) Title: BioIndustrial MII. This solicitation seeks proposals from independent non-profit organizations interested in entering into a Cooperative Agreement or other assistance agreement for the purpose of establishing a state-of-the-art MII in support of biomanufacturing technology.

FOA Type: This document supersedes all previously released information about this program.

FOA Number: FA8650-20-S-5028

Appendices for Funding Opportunities Announcement: Attached to this document are Appendices provided for formulation of the FOA response and informational guidance. If there are any discrepancies between the FOA and the Appendices, the FOA takes precedence.

Catalog of Federal Domestic Assistance (CFDA) Number(s): 12.800 AIR FORCE DEFENSE

RESEARCH SCIENCES

Proposers Day: The Government will hold a Proposers’ Day for this solicitation on Thursday, March 05, 2020 at the Crystal Gateway Marriott, 1700 Richmond Hwy, Arlington, VA 22202 (https://www.marriott.com/hotels/travel/wasgw-crystal-gateway-marriott/). Accessible via Metro.

The purpose of the Proposers Day is to familiarize potential proposers with the concept and vision for the BioIndustrial MII and the associated technology needs. This Proposers Day is for informational purposes only and attendance is not a prerequisite for submitting a proposal. It will provide, however, a valuable opportunity for potential proposers to ask questions and receive answers regarding the solicitation as well as to explore teaming opportunities. The Government is under no obligation to award any related contract/agreement associated with this event. There is no fee to participate and the Government will not reimburse the attendees for any cost associated with participation. No members of the press may attend.

Further details on this event, including registration information, can be found at:

https://BioIndMII.ANSER.org. Questions and answers from Proposers Day will be posted via an amended version of this FOA on beta.sam.gov and Grants.gov.

Note: All questions must be directed via email to Mary Ann Sharits (mary.sharits@us.af.mil) using the subject line: “BioIndustrial MII Questions”.

THIS WILL BE A TWO-STEP SOLICITATION:

First Step: Concept Paper Due Date and Time: The deadline for receipt of concept papers is no later than 3:00 PM Eastern Time (ET) on Monday, 27 April 2020. See Section IV for further information.

Second Step: Full Proposal Due Date and Time: Offerors whose concept papers present an MII approach that sufficiently addresses the needs of the Government will receive invitations to submit full proposals. Invitations for full proposals are expected to be sent by early June 2020.

Prospective offerors will be notified of the due date in a letter of invitation for a full proposal.

See Section IV for further information.

NOTE: Proposal receipt after the due date and time shall be governed by the provisions of FAR 52.215-1(c)(3). It should be noted that this installation observes strict security procedures to enter the facility. These security procedures are NOT considered an interruption of normal Government processes, and proposals received after the above stated date and time as a result of security delays will be considered “late.” Furthermore, note that if offerors utilize commercial carriers in the delivery of proposals, they may not honor time-of-day delivery guarantees on military installations. Be advised: if the U.S. Postal Service is used, this building only receives U.S. Postal Mail twice a week and delivery by that means may not meet the proposal due date and time established herein. Early concept paper and proposal submission is encouraged.

Solicitation Request: This publication constitutes a special competition as contemplated in the 32 CFR Part 22.320. A formal Request for Proposals (RFP), other solicitation, or additional information regarding this announcement will not be issued.

The Government will not issue paper copies of this announcement. The Government provides no funding for direct reimbursement of proposal development costs. Technical and cost proposals (or any other material) submitted in response to this announcement will not be returned. It is the policy of the Government to treat all proposals as sensitive competitive information and to disclose their contents only for the purposes of evaluation.

AFRL is soliciting concept papers, on behalf of OUSD(R&E), followed by technical and cost proposals, on the endeavor described herein. This is a restricted solicitation limited to independent, U.S. non-profit organizations to serve as the award recipient(s) to lead a BioIndustrial MII. The Government encourages small and large businesses as well as academia to participate through teaming arrangements with the lead non-profit organization. Proposals submitted shall be in accordance with this announcement. Offerors should be alert for any amendments to this announcement via beta.sam.gov and Grants.gov that may adjust submission dates or other submission requirements.

System for Award Management (SAM) Registration: System for Award Management (SAM) is the primary Government repository for prospective federal awardee information and the centralized Government system for certain contracting, grants, and other assistance related processes. IT replaces CCR/FedReg, On-line Representations and Certifications (ORCA) and the Excluded Parties Lists System (EPLS). Offerors shall be registered in the SAM database prior to submitting a white paper or proposal. Any awardee must remain registered during the entire project life including invoice submission and through final payment of any agreement resulting from this FOA. Offerors may obtain information on registration and annual confirmation requirements via the SAM accessed through https://www.acquisition.gov or by calling (866) 606-8220.

Type of Contract/Instrument: The Government intends to award a 2 CFR 200 based Cooperative Agreement. The Government reserves the right to award other assistance instruments, if deemed in the best interests of the Government. Cooperative Agreements require successful offerors to have an accounting system considered adequate for tracking costs.

Estimated Program Funding: The Federal Government (DoD) anticipates funding $87.5 million ($87.5M) for this MII, distributed across six fiscal years (FY). It is anticipated that other government agencies will provide additional funds, particularly for the case of basic research support – not subject to cost share - in support of the BioIndustrial MII after award. It is anticipated the recipient will provide $87.5M of industry or other non-federal government funding to meet the expected minimum 1:1 cost share. This sets the total program funding goal at $175.0M. Cost share significantly more than 1:1 offered by industry or other non-federal government funding in order to increase the capability of a BioIndustrial MII will be considered favorably. The anticipated federal program funding by FY is:

Table 1: Anticipated Program Funding ($ Millions)

Fiscal Year

FY20 FY21 FY22 FY23 FY24 FY25 FY26 FY27 Total

DoD Funding

$3.0 $14.0 $17.0 $17.5 $18.0 $18.0 $TBD $TBD $ 87.5 M

Non-Federal Government Cost Share (Expected) $ 87.5 M Total Program (Expected) $175.0 M

Anticipated Number of Awards: The Air Force, in consultation with the OUSD(R&E), reserves the right to award zero, one, or more Cooperative Agreements for all, some, or none of the solicited effort based on the offeror’s ability to perform desired work and funding fluctuations. Only one (1) award is anticipated.

Program Overview: This announcement is to solicit proposals to establish a BioIndustrial MII to serve as a public-private partnership between government, academia, non-profit organizations, and industry to address the spectrum of manufacturing challenges associated with biomanufacturing of non-medical products. The institute will address design-for manufacturing, scale-up production (SUP), downstream processing (DSP), and test and evaluation (T&E). It will also build a resilient ecosystem, focus on ethical, legal, and social implications (ELSI), and advance education and workforce development (EWD). It is recognized that the technical thrust areas will require different considerations and proposers are encouraged to consider how they would prioritize and orient the MII in order to maximize impact to the field.

Through this partnership, the BioIndustrial MII will advance domestic biomanufacturing and support the establishment and growth of supply chain intermediaries within the U.S. that are essential for the bioeconomy. The MII will also serve as a venue to bring together public and private entities in order to examine and advance industry-wide standards, tools, and measurements, ELSI, biosecurity, and biosafety tenants for the responsible usage of this emerging technology. The combination of defense priorities addressable by bioindustrial manufacturing and the commercial potential of these innovations to industry will also require the expansion of a relatively small number of experts into an ecosystem and workforce capable of innovating and supplying U.S. defense and commercial entities with scalable, biomanufactured products. It is strongly encouraged that the BioIndustrial MII collaborate with other MIIs, especially the biomanufacturing MIIs (e.g., BioFabUSA the Advanced Regenerative Manufacturing Institute and the National Institute for Innovation in Manufacturing Biopharmaceuticals (NIIMBL)) to address common challenges, including workforce needs to advance the National Security Innovation Base. However, it is also recognized that while there are numerous defense applications, biomanufacturing is not inherently a defense technology.

The public-private partnership should also include resources across the federal government, and proposers are strongly encouraged to consider how they would collaborate with a wide range of potential public partners beyond DoD.

Manufacturing innovation institutes bring together industry, institutes of higher education, and Federal and State agencies to accelerate innovation by investing in industrially-relevant manufacturing technologies with broad applications. There are 14 MIIs established across the federal government (https://www.manufacturingusa.com/). The current DoD MII network contains eight MIIs, each with a specific technology focus, that is led by a not-for profit organization with U.S. based members from industry and academia. The goal of the BioIndustrial MII is to create an impactful public-private partnership enabling the advanced development and scale-up of emergent biomanufacturing technologies and processes, ultimately transitioning science and technology into defense and commercial manufacturing pipelines.

The Government seeks responses to this announcement that describe the proposed framework, viable business plan, and technical approach for the MII. The Office of the Undersecretary of Defense for Research and Engineering (OUSD R&E) is overseeing this initiative. This particular solicitation, as well as the anticipated award and the management of the BioIndustrial MII, is a cross-agency effort, with the Air Force Research Laboratory having lead responsibilities to execute the solicitation and manage awards.

Communication Between Prospective Offerors and Government Representatives: Dialogue between prospective offerors and Government representatives is encouraged until submission of white papers. Discussions with any of the points of contact shall not constitute a commitment by the Government to subsequently fund or award any proposed effort. Only Contracting/ Grants/ Agreements Officers are legally authorized to commit the Government.

Address all questions to the contracting POC: Mary Ann Sharits, AFRL/RXKMC (mary.sharits@us.af.mil), 937-713-9898. The alternative POC is Christina Smith (christina.smith.33@us.af.mil), 937-938-4899.

Full Text Announcement

I. PROGRAM DESCRIPTION

Air Force Research Laboratory, Materials and Manufacturing Directorate (AFRL/RX), on behalf of the OUSD(R&E), is soliciting concept papers (and later full technical and cost proposals) on the following research effort:

A. STATEMENT OF OBJECTIVE, GOALS, AND NEEDS

1. Objective

The programmatic objective of this solicitation is to select an award recipient to establish a BioIndustrial MII. The BioIndustrial MII will accelerate emergent biomanufacturing technologies and processes with the goal to successfully transition science and technology research into defense and commercial products within a globally competitive U.S. manufacturing ecosystem. The BioIndustrial MII will serve as a bioindustrial innovation hub, providing the infrastructure to support biomanufacturing enterprises of all sizes and ensuring that the U.S.

biomanufacturing industry is a key pillar in an enduring and thriving bioeconomy. Standing up a MII for biomanufacturing will establish U.S. technical leadership, greatly expand U.S. capacity, provide key capabilities to ensure DoD biotechnology modernization, and lead to commercialization of biomanufactured products.

2. Goals

The goals of this MII are to: 1) develop and transition critical, enabling bioindustrial technologies, 2) advance common standards and methods to further the design principles of biological engineering, streamline processes, and modernize T&E to inform future engineering efforts, 3) utilize and contribute to biotechnology data repositories, 4) provide workforce training and education programs to ensure the United States can effectively utilize biotechnology in a broad spectrum of manufacturing environments, 5) advance the biomanufacturing ecosystem handling of ELSI, and 6) strengthen domestic biomanufacturing capabilities.

3. Needs

The challenge of manufacturing products at a commercially meaningful level is a topmost concern for almost all commercial entities operating within the bioeconomy. The United States is a global leader in biotechnology innovation, but the bioeconomy is limited by bottlenecks associated with moving from laboratory prototypes to commercial products. Over the past decade, advances in biotechnology have driven a dramatic increase in the rate of new company formation, but lack of domestic infrastructure and prototyping capabilities along with limitations in test and evaluation of products are still obstacles to biomanufacturing becoming a reliable national resource. Innovations to advance predictable and efficient scale up and downstream processing capabilities are needed to overcome these challenges and move products reliably from the laboratory to the marketplace.

Process intensification is needed to improve the sustainability of biomanufacturing in order to drive commercialization. Additionally, standardization is needed to generate, locate, and leverage data, as well as inform biological designs, train models, predict processes with fidelity, and perform technology transfers. Standardization will also enable the development of methods and metrics to quantitatively assess the quality and performance of intermediates and end products. As with many science, technology, engineering, and mathematics (STEM) fields in the United States, more skilled workers are needed at all levels of education, and each level of training needs to be transformed to be more multidisciplinary and applied. Further, to meet both industrial and national security needs, the MII will need to anticipate the ELSI of biotechnology and resultant products. Finally, the MII will also need to address biosecurity and biosafety components of the technology within biomanufacturing.

4. Addressing Program Challenges

To overcome these challenges, the BioIndustrial MII will address the whole production chain as an integrated process to accelerate innovations in synthetic biology and biomanufacturing. The BioIndustrial MII will do this through improved, standardized, and domestic design-for-manufacturing capabilities, testing and evaluation tools, and a highly trained and skilled workforce, with ELSI considerations throughout. The BioIndustrial MII will improve the efficiency by which biological products are scaled, processed, and evaluated, and the MII will serve to bridge the gap between basic research and product development. The institute will also provide shared assets for companies to access including a secure data repository, as well as state of the art equipment and capabilities. The BioIndustrial MII will create an unparalleled environment to educate students and train workers in advanced biomanufacturing skills.

B. BACKGROUND.

1. MII Purpose. The DoD has established a network of eight MIIs that are managed by OUSD(R&E)/ManTech within the Defense-wide Manufacturing Science and Technology program. MIIs bring together industry, non-profits, and academia with federal and state agencies to accelerate innovation by investing in industrially relevant manufacturing technologies with broad applications. Each MII provides support to propel research and development products to commercialization and economic viability. The MIIs do this by developing and scaling critical technologies in the Manufacturing Readiness Level (MRL) 4 to 7 range. These MIIs are public private partnerships that provide their consortium members with shared access to state of the art equipment and capabilities. The institutes also create an environment to educate and train students and workers in advanced manufacturing skills. Each MII has a specific technical or market focus and serves as a hub of manufacturing with national impact in that focus area, providing the infrastructure necessary to create a highly collaborative environment to spur manufacturing technology innovations which in turn lead to production scale-up and commercialization. Once established, each MII becomes part of the DoD MII network.

2. MII Network Design Tenets. MII design tenets were initially captured in the National Network for Manufacturing Innovation: A Preliminary Design, a White House National Science and Technology Council report issued on January 16, 2013, and subsequently revised by the Department to better align with lessons learned from eight previous DoD Institutes. The current DoD MII design tenets include:

Industry-driven public-private partnerships, led by independent, not-for-profit institutions that strongly leverage existing resources

Federal funding matched by Industry/Academic/State cost share

Domestic industrial commons created through shared IP and facilities

Investments in applied research and industrially relevant manufacturing technologies

Providing access to capabilities for small and medium-sized manufacturing enterprises

Education and Workforce Development investments to promote a robust U.S. ecosystem

MII activities harmonized to meet both DoD and Service modernization priorities and commercial applications

MII size and scale sufficient to provide long-term economic impact

3. MII Critical Functions. Figure 1 illustrates the critical functions of a DoD MII. Although each MII chooses objectives that best serve its own technology ecosystem, all DoD MIIs are expected to pursue the following operational objectives:

Figure 1. DoD MII Critical Functions

a) Hire and Retain Key Management Staff. MII management should be primarily focused on the operation and management of the proposed MII. The MII Executive Director/CEO is expected to be a full-time position and key management staff (e.g., Deputy Directors and other C-Suite staff) give >75% time commitment to the MII.

b) Establish and Manage Physical and Virtual Infrastructure. Although the MII should have access to and leverage a broad range of infrastructure owned by the MII’s member and partner organizations, the MII should establish and operate physical and virtual infrastructure appropriate in scale and capability to the MII’s mission. The long-term cost of operating the infrastructure should be covered by the long-term revenues earned through its operation.

c) Conduct Annual Planning. Employ annual planning processes to incorporate the best ideas, broad stakeholder involvement and involve broad participation in MII activities.

The MII Annual Program Plan must include a detailed budget with a revenue strategy to ensure sufficient funding for core MII purposes. Plans should also include how changes to the business plan will be managed to align with the technology roadmap and enable partnerships with other Federal government agencies.

d) Develop Business Plans to Achieve and Maintain MII Viability. Develop plans to become a financially viable, world‐leading innovation institution. Develop and implement business plans for generating revenue. Bring together private and public entities to develop and accelerate adoption of innovative next generation manufacturing technologies which will lead to increased domestic production capacity, measurable commercialization success, and support national needs. Use these successes to drive continued investment into the MII by both public and private partners.

e) Define MII Structure/Governance. The MII will operate under a non-profit organization but must be sufficiently independent to remain neutral and non‐biased when working with member organizations. Members should recognize the MII as impartial when it makes sub-award determinations and selects representatives to governance bodies. The MII should not position itself to compete with its members for the provision of products and services.

f) Continuously Improve MII Operations. Recognize the economic value and technical innovation created through the establishment of the MII. Build upon those achievements by incorporating technical and programmatic lessons learned to widen the aperture of impactful research and development while retaining a sharp focus on generating real, transformative value. As an element of this focus, continue to develop and periodically update integrated technology roadmaps for research, development, and implementation objectives. Create mechanisms to assess progress towards attaining these goals.

g) Involve Industry and Academia. Define clear and transparent MII by-laws, policies, and strategies for recruitment and active participation of a wide range of members in the MII. Leverage relevant existing private and public sector resources, facilities, national laboratories, university centers, and other government institutions or investments.

Provide a plan to engage stakeholders along the supply chain, including end users, to benefit from the Institute resources and support a strong domestic integrated supply chain. Obtain participation from regional economic organizations such as state and local Governments, development agencies, non-profit organizations, and foundations.

h) Engage with DoD and Other Government Partners. Develop and implement a working relationship with government partners, including participation in decision-making. The MII, as a public-private partnership, will accommodate expectations of the DoD and other Federal government partners to participate in decision making bodies

(e.g., committees/working groups) at both a strategic and technical level. Identify and engage with DoD and government partners to create investment opportunities.

i) Develop Technology Roadmap and Execute Project Calls. Create time and event-based roadmaps for maturing technology areas, including associated manufacturing processes and capabilities as well as R&D. Demonstrate a working, streamlined framework for defining, selecting, and executing projects for all stakeholders. Projects may address technology, manufacturing, workforce development, or demonstration.

j) Foster Education and Workforce Development. Develop an EWD strategic plan beginning with a needs-based assessment and leveraging existing resources to support technical and career education for the bioindustrial workforce. Implement the strategic plan by investing in EWD programs that have a substantial and enduring impact on the availability of a skilled workforce.

k) Develop Manufacturing Technology. Position the MII at the cutting edge of applied research in this technology area and ensure the MII is equipped with the scientific and engineering expertise and access to state of the art equipment and facilities required to achieve this critical function. Conduct R&D and prototyping projects to demonstrate the desired future state for both DoD and commercial customers.

l) Foster Creation of Commercialized Products. The MII should target its R&D investments towards technology development projects, demonstrations, and prototypes that are intended to result in industry partners creating commercially successful products.

m) Create and Maintain an IP-Protected Innovation Ecosystem. Provide for collaboration on pre‐competitive work among multiple parties in a robust Intellectual Property (IP)-protected environment to attract stakeholders to the technology area. Foster the creation and ownership of IP by inventors while protecting background IP and encouraging the IP’s commercialization through licensing and/or productization.

n) Coordinate Development of Industry Standards. The MII should position itself to coordinate the efforts of industry and relevant Standards Development Organizations to identify the need for new or revised standards and accelerate the development of those standards.

o) Generate Cost Share and Continued Investment. Attract cost share by proving the MII’s value to industry, academia, and state and regional stakeholders. Cost share from members or stakeholders adds to the manufacturing innovation ecosystem and is needed to ensure a vibrant domestic manufacturing base. The MII should engage the ecosystem in ways that stimulate continued investment in relevant technologies through both the MII itself and the larger biotechnology industrial base.

p) Enhance Defense Capabilities. As a DoD-sponsored institute, the MII should engage with DoD partners to include DoD modernization priorities and defense applications in the MII’s technology roadmaps. Manufacturing technology development projects should strive to enhance defense capabilities. Technologies with both defense and commercial applications should be pursued when they can contribute to defense capabilities while also serving larger commercial markets.

C. PROJECT OVERVIEW

1. BioIndustrial MII The BioIndustrial MII will create an end-to-end innovation ‘ecosystem’ in the United States to advance the state of biomanufacturing for non-medical applications.

Current domestic and global capabilities are focused on an array of diverse product classes.

However, the time and cost required to scale up and isolate these biomanufactured products is typically prohibitive, and generalized manufacturing capabilities do not yet exist to support advanced classes of products needed for defense applications. The BioIndustrial MII will advance biomanufacturing technologies for a variety of small molecule and macromolecular product classes, as well as complex products involving self-assembly, metal coordination, whole cell products, and products that may need to be further processed by traditional chemical processes or other means (e.g., additive or subtractive manufacturing techniques). These technologies may include fermentation, cell-free production, product extraction and purification, materials processing and testing, and data-driven design capabilities throughout the product development cycle. While the MII will have capabilities across the design-build-test-learn cycle (DBTL), special emphasis on efficient scale up and separation technology development across multiple classes of products should be maintained given current industrial challenges (Technical Thrust Areas 2 and 3).

The BioIndustrial MII will become a definitive source of biotechnology data, collated and cross-referenced from disparate sets of information. Together these data will be integrated into a system that enables MII operation and success. Complexities of the multivariable nature of biomanufacturing will be overcome through use of computational methods and models, to include artificial intelligence/machine learning, to process existing and future data and to streamline process development and T&E pipelines.

The BioIndustrial MII must bring together the resources and developmental potential of the Federal Government, academic institutions, Original Equipment Manufacturers (OEM) and other manufacturers, synergistic technology contributors, and state and local governments to achieve the vision of advancing non-medical biomanufacturing. Essentially, the BioIndustrial MII ecosystem will assemble broad interdisciplinary members into a cohesive unit that provides access to advancements across multiple technology thrust areas. To enable success, the BioIndustrial MII should collaborate closely with other MIIs to include bidirectionally sharing technology and holding joint project calls.

The BioIndustrial MII will allow Government, industry, and academia to come together with the goal of organizing U.S. capabilities in biomanufacturing technology to better position the United States relative to global competitors. It will also enable academic institutions and industry partners of all sizes to participate and benefit from the BioIndustrial MII’s collaborative manufacturing advancements. The BioIndustrial MII will address both DoD and commercial applications, with a focus on maturing technologies from MRL 4 1 to MRL 7 2.

In addition to the technology thrust areas of the BioIndustrial MII, there are domestic supply chain and infrastructure needs that should be addressed. While some biotechnology products are made in the United States, many products are produced and processed overseas because foreign facilities often have lower site operating costs or lower raw material costs. Additionally, the United States lacks cost-competitive Contract Manufacturing Organizations (CMO) that can perform specialized fermentations often required for products in the bioeconomy. Because no new construction is allowed with MII federal funds, the BioIndustrial MII consortium should include a dedicated focus on supporting large-scale fermentation capacity through cost-share and/or retrofitting of existing manufacturing facilities for fermentation, product recovery, and product purification.

2. Scope Synthetic biology and biomanufacturing have the potential to make molecular targets at a reduced cost, with less logistical burden, and with better performance than molecules and materials obtained from traditional manufacturing approaches. The BioIndustrial MII is meant to capitalize on this potential and further accelerate US growth in this area, which will contribute to the bioeconomy. The Government expects the BioIndustrial MII to support an end-to-end ecosystem in the United States for biomanufactured products for non-medical use. These products will include small molecule, macromolecular, protein, and whole organism products to be used and/or further processed for a vast array of non-medical applications. Specifically, the Institute should develop capabilities and technologies for the production and scale of materials and processes from engineered biological systems.

The BioIndustrial MII will facilitate the design, manufacture, and testing of new combinations of products or cells, explore improvements in manufacturing technologies in biology, and develop end-item products through use of a collaborative infrastructure. The Government envisions that this MII will leverage industry cost share through its membership to provide access to scale-up and separation infrastructure, expertise, and services necessary to realize end-item prototypes that can be tested and evaluated for commercial and defense applications. The BioIndustrial MII will facilitate matching defense and commercial needs and requirements to the most appropriate materials and/or applications, thus enabling promising new products to reach the market.

A key role of this MII is its relationship with member reagent, raw material, and equipment suppliers. The BioIndustrial MII is expected to develop and refine its competency in value stream analysis, be able to identify gaps in the supply chain, anticipate failure nodes in supply chains, and develop solutions to address how gaps or vulnerabilities can be filled. The MII should also have the ability to secure the supply chain for a wide range of products via biomanufacturing from domestically-sourced feedstocks and reagents when possible. The Bioindustrial MII will leverage knowledge of the biotechnology sector and act as an intermediary between users, researchers, and manufacturers to enable the development of more

1 MRL 4: The technology produced in the laboratory environment has been independently reproduced, predictions have been validated for key parameters, and an initial manufacturability assessment has been completed 2 MRL 7: Technology produced in a production representative environment robust and effective manufacturing supply chains based upon product needs. By developing innovative manufacturing technology solutions, the MII can help establish and configure new domestic supply chains for products previously sourced from foreign entities, or from non-biomanufactured sources.

3. Schedule

a) The period of performance is eighty-four months for all activities associated with this MII award. After award, the MII should develop plans for long-term financial viability beyond the initial FOA award.

b) It is also important that the MII describe their plans for the rapid stand up of essential MII operations, the creation, assessment, and completion of technical projects it will undertake, as well as proposed educational and training programs. Initial operations activities include hires, membership agreements, finalizing cost share commitments, opening the MII facilities, establishing a governance structure, developing an intellectual property plan, executing quick start projects, initial technology roadmapping leading to a first project call, and all other activities required to establish the MII.

D. TECHNICAL OBJECTIVES Essential to the BioIndustrial MII effort are the details on the conceptual technical scope of research and development, as specified in the evaluation criteria. The overarching technical goal for the BioIndustrial MII is to create and operate an ecosystem that fosters technological innovation in synthetic biology-enabled manufacturing from design to manufacture of products. To that end, the BioIndustrial MII will focus on five focused thrust areas: (1) Data and Design, (2) Scale-Up Production, (3) Downstream Processing, (4) Test and Evaluation, and (5) Resilient Biomanufacturing Ecosystem Development. The MII will also address EWD along with ELSI. Figure 2 presents the technical concept of the Biondustrial MII.

Figure 2. Bioindustrial MII Technical Concept

1. Bioindustrial MII Thrust Areas

a) THRUST AREA 1 – Data and Design. The BioIndustrial MII will require a centrally controlled, comprehensive unified infrastructure. This will include an integrated approach to the DBTL cycle from proof-of-concept to on-demand manufacturing.

Process-driven workflows (e.g., gene/pathway selection, DNA amplification, DNA sequencing, assay design) should be linked to complex procedures (e.g., strain transformation/transfection, fermentation process development, analytics) on diverse instrumentation for consistent outcomes. This unified computation infrastructure will enable the shared use of developed robust datasets along with standardized models, common resources, and AI/ML algorithms for organism and process optimization. Strain engineering and product development services should be made available to traditional chemical or material manufacturers seeking to utilize biological manufacturing in addition to their traditional supply chains.

1. Sub Thrust Area 1a – Digital Backbone. A need exists for an interoperable and extensible data ecosystem built on a containerized platform that can bridge the differences between varying technologies and facilities. The data ecosystem should be enabled by harnessing standardized vocabularies, data models, and interchange formats around Representational State Transfer (REST) architectural style for distributed hypermedia systems, application program interfaces (APIs), and FAIR (Findable, Accessible, Interoperable, Reusable) data. Building this type of digital backbone would provide non-profit and industrial scientists with access to the experimental and data resources therein. It would also dramatically accelerate the transfer and adoption of best practices that are encapsulated in these shared and reusable process design and data objects.

2. Sub Thrust Area 1b – Comprehensive Biotechnology Dataset. The computation ecosystem will need to support standard experimental processing pipelines and conventions for metadata reference and storage. This should include means to process existing data into standard conventions that will allow for unified analyses of data from numerous experiments and sources. These processes should allow automated methods to pull data from multiple, currently incompatible sources (e.g., gene databases, plasmid databases, biological parts databases). In addition, unified data should include processing standards for all data and metadata.

3. Sub Thrust Area 1c – Predictive and Comprehensive Data Analytics. Machine learning and data analysis algorithms should attempt to combine data streams in order to create an automated system that includes predictive models for strain optimization, global process optimization, and inclusion of quality assurance algorithms.

Computational approaches will need to leverage data generated from SUP and DSP screening approaches, along with published data and physical property prediction models to optimize candidate processes to meet target yield, purity, and productivity goals.

4. Sub Thrust Area 1d – Strain Engineering. Metabolic engineering will be required to onboard pathways into MII chassis strains, or adapt member or customer strains to

MII production requirements. Additional DBTL rounds of strain engineering will be required to improve target molecule titer, reduce DSP requirements, and other forms of optimization required to advance the TRL/MRL of member and customer products.

b) THRUST AREA 2 – Scale-Up Production (SUP) To increase the use of engineered organisms in manufacturing, the community needs better tools for scale-up manufacturing, including models to relate lab-scale and full-scale fermentation, analytics, and reactors that monitor and adjust growth conditions, metabolites, yield, and other parameters in real time.

(1) Sub Thrust Area 2a – Real-Time, Automated Sensors. The central part of any next-generation manufacturing environment should be an ecosystem of connected, reconfigurable automation pipelines, integrated sensor networks, and artificial intelligence (AI) computing. This framework will enable real-time feedback to equipment that can correct, optimize, and scale both scientific and process outcomes.

This ecosystem should be enabled by a network of machine-readable components and built-in algorithmic quality assurance.

(2) Sub Thrust Area 2b – Rapid On-Boarding of Organisms for Manufacturing.

While large biofermentation companies utilize a limited number of metabolically optimized chassis strains, smaller companies, academic, and non-profit groups use a wide array of organisms. Advancing onboarding of member-designed chassis strains will be essential. Tool development will be required to adapt member organisms to MII fermentation requirements. In addition, reconfigurable, modular fermentation equipment could be adapted to meet the requirements of new chassis strains. An innovative combination of adaptable infrastructure and engineering strategies should facilitate inclusion of a broad range of potential chassis organisms. Comprehensive data/metadata analysis and capture will ensure that lessons from onboarding new strains are incorporated into future engineering efforts. Standardization of genetic engineering across species will enable reconfigurable genetic circuitry for rapid prototyping of multiple chassis organisms in parallel. Connections to efforts in basic research and early applied research will accelerate establishment of these capacities.

(3) Sub Thrust Area 2c – SUP Infrastructure. Next-generation scale-up and pilot facilities will be required to design proper media and predictably engineer organisms that will efficiently produce target molecules. Development of bench scale bioreactors (1-10 liters (L)) and pilot scale bioreactors (hundreds of L) will be designed to reproduce the conditions encountered in a larger fermentation (thousands of L). These pilot scale bioreactors will be linked to analysis pipelines that evaluate carbon flux to ultimately inform the next generation of strain design. Additionally, strategies will be implemented to retrofit existing domestic infrastructure (e.g., industrial fermentation capacity) for biomanufacturing.

c) THRUST AREA 3 – Downstream Processing (DSP). DSP refers to post-fermentation characterization, processing and purification of biosynthetic products. In order to advance biomanufacturing, separation techniques need to be scalable and commercially viable. It is also essential to confirm that desired yield, purity, and productivity targets have been met for biosynthesized products.

(1) Sub Thrust Area 3a – Robust, Automated Experimentation Platforms. Advances in autonomous experimental platforms are sought to address: challenges with product isolation and purification (e.g., optimization, combining techniques); high throughput screening of multiple experimental conditions; and, accelerated yet complete learning from test cycles. Investments in miniaturization, automation, high-throughput measurement (which is not possible with DSP sample streams today), and computation may lead to shorter cycles of iterative learning and therefore reduce development costs.

(2) Sub Thrust Area 3b – Recovery Approaches for Complex or Intracellular Products. Establishing scalable extraction and purification processes for small molecules is already an important challenge in the field. Fundamentally new, modular chemical engineering technologies need to be developed to isolate products from diverse cell types and purify them. This may lead to chemical/biological class-specific processes and would broaden the application of biomanufacturing to wider classes of products.

d) THRUST AREA 4 – Test and Evaluation The ability to rapidly assess and characterize emergent molecules, materials, and cells across a battery of tests and evaluation procedures will be critical, and will also facilitate identification of novel applications (including defense applications) for biotech-enabled products. The required evaluation platforms present major challenges, in part because of the sheer diversity of new materials, molecules, and cells that will emerge from design-build-test biotechnology platforms. Comprehensive T&E platforms that harness state-of-the-art analytical tools for characterization, assessments, and measurements of biologically produced molecules, materials, and cells will underpin successful biomanufacturing of these types of products.

(1) Sub Thrust Area 4a – Cellular T&E, High-Throughput and Low-Cost Culture Formats. Culture volumes should be sub-L with tunable parameters to mimic manufacturing-scale conditions (e.g., controlled feed, oxygen delivery, etc.). The culture formats should be low-cost and deployed on a large-enough scale to ensure that biological libraries can be effectively sampled.

(2) Sub Thrust Area 4b – Cellular T&E, High-throughput Non-Destructive Assays.

Analytical readouts should require low sample volumes to increase throughput and data acquisition. Additionally, readouts should be broadly applicable to simultaneously measure a wide range of final products, pathway intermediates, feedstock, and byproducts. Measurements should be collected continuously or with high frequency to sample biological diversity and subsequent product formation with high resolution and speed.

(3) Sub Thrust Area 4c – Molecule and Material T&E, Property and Performance.

Platform technologies for evaluation of chemical, thermal, physical, mechanical, optical and other properties of interest of emergent molecules and material precursors are necessary. High-throughput evaluation methods to assess and sort or filter desirable properties coupled to automated analysis and data processing of T&E platforms will extract key parameters that accurately predict desired properties of end products. Meta-analyses will inform future design cycles for various classes of biomolecules.

e) THRUST AREA 5 – Resilient Biomanufacturing Ecosystem. The BioIndustrial MII will need to integrate cyber security protections into the core data platform, experimental infrastructure, and networking equipment used to connect disparate devices. The security protections should address all aspects of a typical manufacturing environment as well as those unique the BioIndustrial MII, including distributed infrastructure, bio-computational interfaces, and domestic supply chain security. In order to instill confidence and ensure maximum participation by the community, the MII will need to adopt internal cyberphysical security precautions to protect data as well as define standards for acquisition of raw materials and feedstocks from suppliers.

1. Sub Thrust Area 5a – Integrated Cyberphysical Security. In addition to basic cybersecurity requirements that underlie all thrusts, this specific subthrust addresses the implementation of cybersecurity technologies into all data platforms, control systems, and electronically-controlled devices to create an integrated cybersecurity solution for all systems associated with the MII. A sensor network that produces cyber security logs for all interconnected devices and systems will enable detection of intrusions and cyberattacks. Additionally, infrastructure should be developed to aggregate cyber security data, search logs, and apply algorithms for detection and forensic purposes. The MII should leverage commercial security technologies, containerization approaches, and integration frameworks to create a robust cybersecurity solution. The MII will likely need to adopt and tailor existing infrastructure to collect and protect data.

2. Sub Thrust Area 5b – Domestic Supply Chain for Critical Raw Materials. The ability to create and sequence engineered genetic constructs and peptides constitutes critical components for biomanufacturing. Accompanying these reagents is sensitive digital information that could reveal details of the manufacturing projects. Therefore, domestic infrastructures/suppliers for DNA synthesis, sequencing, peptide synthesis, and protein sequencing must be part of the MII. Domestic sources for other critical materials, reagents, and feedstocks should be required when available.

2. Ethical, Legal, and Social Implications (ELSI). BioIndustrial MII success will not rest solely on technical achievements. For MII-developed technologies to be broadly utilized, the BioIndustrial MII will need to focus on the ethical, legal, and social implications of synthetic biology, as well as employ and advance biosecurity and biosafety standards. These practices may require additional research and development to address the evolving nature of the field.

a) ELSI Plan. The MII will need to examine national and international policies that address accessibility, public concerns, and a range of other relevant topics. Some of these policies are already established, but the scientific landscape is rapidly changing, and there is a growing acknowledgment that governance and oversight structures may need to be modified or created in order to stay abreast of the science. It will be necessary to provide evidence-based education that can inform the public and future policy development to prevent misconceptions as well as misuse of synthetic biology.