Regenerative Medicine (REGEN) RPP

Purpose

Applications for this Request for Project Proposals (RPP) are being solicited for the Defense Health Agency, Research, Development and Acquisition (DHA RDA) Directorate. As directed by the Office of the Assistant Secretary of Defense for Health Affairs (OASD(HA)), the DHA RDA Directorate manages the Defense Health Program (DHP) Research, Development, Test, and Evaluation (RDT&E) appropriation.

This solicitation, issued by MTEC, represents an RPP for MTEC’s support of the Clinical and Rehabilitative Medicine Research Program (CRMRP) technology objectives. Strategic oversight for the award(s) supported via this RPP will be provided by Joint Program Committee 8(JPC-8)/CRMRP. To address the President’s Advanced Manufacturing Partnership, funds are being made available to support emerging technologies and foster a domestic manufacturing capability that could increase jobs and position the U.S. as a leader in specific domains. As such, funds from the DHP RDT&E appropriation are being made available to advance the state-of-the-art in biomedical manufacturing, consistent with the National Strategic Plan for Advanced Manufacturing. Specifically, funds are to support areas of regenerative medicine manufacturing and prototyping that require development and harmonization into reproducible, consistent procedures that could stand the test of U.S. Food and Drug Administration (FDA) approval. This emerging area of medical technology and innovation suffers from the lack of standard manufacturing procedures that support this combination product line. This initiative is intended to have a period of performance of up to five years. Outcomes from this initiative are anticipated to result in well-defined and sufficiently advanced prototypes and manufacturing technologies that may be included in regulatory applications seeking FDA approval.

As the solicitation will describe, MTEC has bucketed the potential areas of improvements, and hence proposals, for this requirement into five categories. MTEC believes all of these areas currently present roadblocks to regenerative medicine prototype development and product manufacturing that will need to be addressed over the life span of the funding, and MTEC will endeavor to balance the portfolio of projects across all these areas as best as possible. These are as follows:

1. Development of universal, defined culture media for regenerative medicine.

2. Bioreactors to enable efficient and cost-effective cell and tissue expansion for regenerative medicine products.

3. Cell, tissue, and product preservation for regenerative and personalized medicine.

4. Large scale manufacturing and quality assurance of regenerative medicine based products.

5. Dynamic and innovative quality assurance strategy for regenerative medicine manufacturing.

Later within the solicitation these areas will be described in more detail, and specific examples will be provided of the type of actions that are being requested. Any of these areas may be selected as potential areas for a proposal focus.

As funds are being made available through the DHP RDT&E appropriation, military relevance is a critical component of proposal submission. The CRMRP focuses on innovations to reconstruct, rehabilitate, and provide definitive care for injured Service members. The ultimate goal is to return the Service members to duty and restore their quality of life. Innovations developed from CRMRP-supported research efforts are expected to improve restorative treatments and rehabilitative care to maximize function for return to duty (RTD) or civilian life. The CRMRP interest is in medical technologies (drugs, biologics, and devices) and treatment/rehabilitation strategies (methods, guidelines, standards, and information) that will significantly improve the medical care provided to our wounded Service members within the DoD health care system. Implementation of these technologies and strategies should improve: the rate of RTD of Service members, the time to RTD, clinical outcome measures, quality of life, as well as reduce the hospital stay lengths, clinical workload (patient encounters, treatments, etc.), and initial and long-term costs associated with restorative and rehabilitative or acute care. The CRMRP focuses its efforts on the following research areas: neuromusculoskeletal injury (including amputees), sensory systems (including hearing, balance, tinnitus, and vision), acute and chronic pain, and regenerative medicine. This MTEC RPP is focused on the clinical, prototyping, and manufacturing needs of the regenerative medicine research and development portfolio. Though advancement in prototype development and manufacturing practices is the primary goal, the product being advanced should have relevancy to the military’s regenerative medicine needs. Offerors who wish to advance prototype development and manufacturing process standardization called for in this solicitation should use regenerative medicine product lines that are within the groups below for their sample materiel. In that manner, the project requirement includes two simultaneously critical objectives: 1) improving the manufacturing process, and 2) making available product for applied research or clinical studies.

In order to qualify for an award under this RPP, the project must fall within the prescribed areas of military need which has a manufacturing component aspect to continue its development. Example areas of military need are: composite tissue regeneration, vascular repair/revascularization, nerve regeneration, bone regeneration, muscle protection/regeneration, treatment of burns and large skin injuries, immunomodulation, and regeneration of the genitourinary system.

The manufacturing effort is the primary driver, but that product which will be produced within the manufacturing processes and validation testing should be one that meets military need. A couple of factors become evident when seen through this perspective:

• Later stage projects would be the most relevant to this solicitation. Later stage projects have a far greater need for this type of manufacturing scale up and standardization to support the project development plan. MTEC, therefore, expects that projects should be either entering formal FDA supportive clinical trials or working within defining animal studies for upcoming regulatory submission to the FDA. This is not meant to support pilot lot manufacturing for animal study purposes.
• It is expected that many of the actual regenerative medicine projects may still be at the academic level, yet the manufacturing requirements demanded are most suited to industry. MTEC, therefore, considers that a teamed approach may have the greatest level of success, especially considering that the eventual goal is to transition products to industry for FDA approval.

Finally, another factor that should be considered is the dual use opportunity of this work. The funds provided for this biomanufacturing initiative are to prime the pump for such efforts, but are not anticipated to be the sole funding resource for the efforts. Because the area is largely focused at the industry prototyping and manufacturing capabilities, rather than academic discovery actions, it is anticipated that the Government funds would provide incentive for industry funding to join the project. While not a requirement, Offerors are strongly encouraged to discuss outside funding potential prior to submitting proposals.

Scope of Work

Technology Objectives

The JPC-8/CRMRP, DHA RDA, and OASD(HA) have identified a need for regenerative medicine prototype development efforts and manufacturing technologies. Current Good Manufacturing Practice (cGMP) quality is a requirement by the FDA and European Medicines Agency to provide patients with clinical-grade products that are safe and have defined quality characteristics. However, standardization and robust manufacturing techniques are lacking in regenerative medicine, which will continue to impede progress in advancing regenerative medicine based technologies and treatments toward the clinic. This is likely due to many factors that need to be developed and advanced, including (1) development of universal, defined culture media, (2) advancing bioreactor technology for cost-effective cell and tissue expansions, (3) improving cell, tissue, and organ preservation technology, (4) innovating and advancing large scale manufacturing and quality assurance for regenerative medicine based products, and (5) developing dynamic and innovative quality assurance strategies for regenerative medicine manufacturing. Based on this, the major objective of this solicitation is to develop scalable, production-ready commercial prototypes and processes for cell, tissue, or organ bioengineering technologies that will overcome current challenges and enable successful cGMP manufacturing and clinical translation of regenerative medicine based therapies. Technologies of interest include, but are not limited to, the following:

1. Development of universal, defined culture media for regenerative medicine.

Many regenerative medicine products, particularly for musculoskeletal applications, include a cellular component. The cellular component is typically derived from an autologous or allogeneic source. These cells are living products that are passed through a variety of processing steps, including biopsy, cell banking, expansion and scale-up, storage, and distribution. Throughout these many processing steps, the complex mixture of culture media can significantly vary among cell types and process steps (e.g., expansion, cryopreservation, differentiation). In addition, serum is also a very complex mixture containing xenogeneic ingredients, where batch-to-batch consistency is of great concern and often has unwanted effects on the optimal production of cells. Therefore, there is a need to develop universal, xeno-free media formulations for cell types commonly used in regenerative medicine products. In addition, GMP-quality human enzymes or extracellular matrix proteins should be used if required during the process. Specific areas of interest include, but are not limited to, the development of:

• Xeno-free serum.
• Xeno-free defined cell medium for cell growth, selection and expansion, differentiation, storage and distribution, and specimen harvest.

2. Bioreactors to enable efficient and cost-effective cell and tissue expansion for regenerative medicine products.

For many regenerative medicine therapies, millions of cells are required for each patient. The cell and tissue expansion phase of the manufacturing process is by far the most expensive and time consuming step, often requiring several months to reach economically-viable numbers of cells. There is a significant need for alternatives to flat plate culture technologies for efficient and cost-effective cell and tissue expansion. Areas of interest to enhance cell expansion for regenerative medicine products include, but are not limited, to:

• Scale-up of commonly used cell types with defined quality characteristics into 10L, 50L, and 100L bioreactors.
• Non-invasive or minimally-invasive in-process technologies that can monitor key parameters of the expansion process, including but not limited to: cell viability, cell number, endotoxin content, mycoplasma.
• Non-destructive cell harvesting technologies.
• Single-use bioreactors for the scale-up of cells.
• Infrastructure to allow cell expansion to occur in parallel.
• Cell purification processes.
• Scale-up of the production of organoids for industrial use.

3. Cell, tissue, and product preservation for regenerative and personalized medicine.

Biobanking and biopreservation offer the possibility to preserve cells and tissue sources for future use. For regenerative and personalized medicine, these cells and tissues are later developed into products that need to be preserved to maintain activity during production, through manufacturing release, and ultimately, to patient application. Therefore, there is a need to develop advanced, cost-effective technologies and processes for banking cells and tissues, and preserving regenerative medicine-based products to assist with shipping and distribution. Areas of interest include, but are not limited, to:

• Novel preservation methods (e.g., non-cryogenic) that can be used on tissue engineered products during storage, shipping, and distribution (including adverse environments such as austere conditions).
• Advanced systems and processes for cell and tissue preservation, including specimen harvest, cell retrieval, and tissue-typing.
• Tests or methods to analyze or determine cell, tissue, or product viability/function following short-term and long-term storage.

4. Large scale manufacturing and quality assurance of regenerative medicinebased products.

Regenerative medicine products in early development are often fabricated using laboratory-based processes and lack defined product specifications. Therefore, the intent of this area of interest is to transfer these laboratory-based processes into scalable, production-ready, commercial manufacturing processes for cell, tissue, or organ bioengineering products with defined acceptance criteria. Specific areas of interest include, but are not limited, to:

• Scalable, production-ready, commercial additive manufacturing, such as 3D printing for regenerative medicine applications.
• Automated tissue digestion systems.
• High throughput cell sorting technology.
• High throughout cell separation/isolation from media.
• Automated manufacturing processes for regenerative medicine products (scaffolds and/or bioactive molecules and/or cells).
• Develop large scale systems capable of screening and engineering adult stem cells.

5. Dynamic and innovative quality assurance strategy for regenerative medicine manufacturing.

The identification and specification of standards and acceptance criteria are important for the regulatory approval of all implantable, manufactured products. Regenerative medicine-based products tend to have qualitative product acceptance criteria, which are difficult to standardize. Therefore, there is a need to develop and advance methods for quality assurance to assess process changes in regenerative medicine product manufacturing as well as in cell, tissue, and bioengineered organ product characteristics and function. Areas of interest to enhance the quality assurance strategy of regenerative medicine products include, but are not limited, to:

• Systems that can provide rapid batch testing for the evaluation of a production run.
• Automated and non-destructive imaging systems for inspection and characterization of tissue engineered products.
• Non-destructive in-process technologies that can monitor key parameters of the manufacturing process.

Points of Contact

For inquiries, please direct your correspondence to Biomedical Research Associate Chuck Hutti, Ph.D. at Chuck.Hutti@ati.org.