Establishing a Current Good Manufacturing Practice Facility for Biomaterials and Biomolecules in an Academic Medical Center

Abstract

A major hurdle in translating biomaterial-based products is moving from the laboratory into first-in-human trials. For many investigators, this is difficult to achieve without industry assistance. A biomaterials facility that follows current good manufacturing practices (cGMPs) in an academic medical center would potentially accelerate the process of translating biomedical products to first-in-human trials. This article details the establishment of Mayo Clinic's Biomaterials and Biomolecules cGMP facility and the challenges encountered in creating a manufacturing facility in an academic medical setting. The facility functions as a platform for manufacturing and as a resource for guiding investigators from discovery through translation. The success of the facility relies on addressing challenges associated with balancing the volume of requests for cGMP services and the facility's capacity by prioritizing projects in the pipeline. In addition, we will educate researchers regarding the methodologies used in carrying out their preclinical projects such that the data generated are appropriate to support an Investigational Device Exemption application to the Food and Drug Administration.

Impact Statement

This article describes the feasibility and path to establishing a current good manufacturing practice biomaterial facility in an academic medical center. It presents a solution to overcome the “Valley of Death” in bench to bedside translation of biomaterials-based medical devices. It sets a good and feasible example to those who are interested in joining the path toward clinical practice/commercialization, and helps to spur other institutions and investigators to think about how they could incorporate in-house processes and facilities to help speed up the translation of their work into first-in-human trials.

Introduction

New biomedical and technological innovations hold great promise for many patients for whom standard-of-care is not sufficient treatment, or for whom no treatment exists. Many of these discoveries and inventions are on the cutting edge of biomedical research, including hydrogels, biodegradable polymers, and three-dimensional printed products.^1–7 These biomaterials can be applied in the repair of a wide range of tissues including, but not limited to, bone,^1,6,7 cartilage^4,7 muscle,³ skin,^5,7 cardiac tissue,² and nervous system.⁷

Although most investigators can envision how their work could improve clinical practice, the path from an academic medical research setting to the clinic is not well defined. Consequently, a large proportion of novel research falls short of moving into first-in-human trials. The term “Valley of Death” refers to the transition points between basic and preclinical research on the one hand, and first-in-human translational studies on the other hand.^8,9 In this article we present a case study of the establishment of a Biomaterials and Biomolecules facility that follows current good manufacturing practices (cGMPs) within an academic medical institution with the aim of spurring discussion at other institutions regarding the utility of such facilities in speeding translation of novel biomaterial products from bench to first-in-human trials.

Why Create a cGMP Facility in an Academic Medical Center?

On average, it takes 17 years to move a drug or biologic from bench to bedside.^10–12 Surgical device translation is equally slow. Only 9.8% of 205 devices identified in the literature successfully translated to the clinic at the 10-year mark.¹³ Early clinician involvement was a significant predictor of successful translation. Products for which there was early input from clinicians were six times more likely to be successfully translated.¹³ However, authors who published positive findings involving biosynthetic polymer nerve scaffolds found that the principal barrier to translation was the lack of a commercial/industry partner.¹⁴ The above observations indicate that the absence of early, continuous collaboration between clinicians and industrial colleagues is the biggest obstacle to the successful translation of a novel surgical device to first-in-human trials.

Previous legislation in the United States has targeted this challenge in crossing the bridge between academia and industry. One of the earliest pieces of legislation was the Bayh-Dole and Stevenson-Wydler Acts that became law in 1980 and aimed to encourage the collaboration between academia, government, and industry.^9,12 The Act permitted intellectual property arising from government-funded research to be assigned to a university, a nonprofit organization, or a company. Similarly, the Act required federal laboratories to set aside part of their budget to engage in transfer of their intellectual property to the private sector; in effect, it was the first technology transfer law.

There have been several additional technology transfer acts in the years since Bayh-Dole and Stevenson-Wydler, all of which have aimed at enhancing the likelihood that taxpayer-funded research would result in improvements to the economy. These have included the Federal Technology Transfer Act of 1986, the Small Business Technology Transfer Act (1992), the Small Business Research and Development Enhancement Act added the NIH Small Business Innovation Research grant mechanism (1992), and amendments to the Stevenson-Wydler Act (2007) by the America COMPETES Act (America Creating Opportunities to Meaningfully Promote Excellence in Technology, Education, and Science). For many investigators, such collaborations that form under the legislation described above entail transferring a majority of responsibility for the research to an industry partner. This would place the investigator in a partnership role in the project over which their industrial partner had near-complete autonomy.

One solution is to create a resource to manufacture novel medical products within academic medical centers to facilitate the ability to conduct first-in-human trials without reliance on an industry partner. A major challenge in carrying out such a solution, however, lies in the fact that academic facilities often depend on industry partners to provide manufacturing support, including appropriate cGMP facilities, to develop their investigational product to meet safety and quality standards needed for first-in-human use. The formation of a partnership with industrial colleagues is an important step in the path toward population-wide availability of the product in question. However, the timing of that collaboration becomes more flexible if the researcher-inventor can proceed to and beyond the first-in-human translation if she or he feels that it is optimal during the development of a particular product to do so.

To do so, it is necessary for investigators to have ready access to cGMP facilities in-house. This may eliminate some of the challenges of working through a contract manufacturing organization and increase investigator focus on the device, biologic, drug, or combination product design to obtain regulatory approval for first-in-human clinical studies. The prioritization of the Food and Drug Administration's (FDA's) Early Feasibility Study program for products submitted through the Center for Devices and Radiological Health, coupled with an Investigational Device Exemption presubmission dialog with the FDA, affords investigators the opportunity to have direct interaction with the FDA regarding their product.¹⁵ This allows discussion of the first-in-human investigational study before device design and testing is being completed. In addition to the physical facility, it is also necessary to recruit support personnel who are proficient with the application of both cGMP and regulatory requirements to first-in-human trials.

To accomplish our goal of establishing a biomaterials cGMP facility within our institution, we began with an initial assessment of existing available facilities and resources. As part of our planning process, we consulted with a few academic medical institutions with known cGMP facilities to determine how they approached the establishment and management of their facilities. We then began planning the clean room design within an existing research building on campus, focusing on addressing cGMP and regulatory requirements and on ensuring the facility could be adapted to accommodate a variety of biomaterials-based products.

Initial Assessment and Planning

A gap assessment was conducted to determine the specifications required to manufacture medical products within the Mayo Clinic Center for Regenerative Medicine (CRM). The gap analysis was a means of determining whether the current facility or system meets the necessary requirements and clean room standards to achieve desired outcomes and, if not, what areas need to be further developed or newly created. The result was that the facility would leverage an existing Mayo cGMP facility, the Human Cell Therapy Laboratory (HCTL), and its associated Quality Management System as a benchmark. The CRM, together with the institution, made the decision to establish a biomaterials and biomolecules synthesis and fabrication facility on the Mayo Clinic campus in Rochester, Minnesota.

A multidisciplinary design team was assembled to ensure that the facility was under the appropriate manufacturing and quality regulations and standards to address the unmet needs of potential investigators: their intended service lines, their products, and the processes associated with those products. This team included members of the Mayo Facilities team, the HCTL, a design firm with cGMP facility expertise, and the future Biomaterials and Biomolecules cGMP facility staff.

Lessons Learned from Specific Institutions

To better understand manufacturing on a larger scale, members of the design team toured cGMP facilities associated with three other national academic medical centers and commercial enterprises. Although there were no biomaterials facilities based solely at a university or academic medical center at that time, there were academic medical center cGMP facilities for biological and cellular products that kindly welcomed a site benchmarking visit by our team.

A major private research institution and academic medical center found itself facing a similar problem of moving positive research findings into the clinic. To solve the need for a cGMP facility to support first-in-human studies, this particular academic medical center formed a company entirely within their institution. The facility is located on the same campus as the medical center.¹⁶ Since 2003, the facility has expanded to include 21,000 square feet of clean room space and space for air handling, laboratory, and offices. This facility focuses solely on projects within the institution and manufactures both biological and cellular products.

The first important concept that our visiting team gleaned from this particular academic facility was the necessity to implement and independently manage a dedicated quality control and assurance program that would eliminate any potential conflicts of interest. Second, the proximity of a clinical processing facility for cell and blood products, managed under the same quality system, allowed the company to support a broad array of biological products.¹⁷ Third, the creation of a cGMP Research Advisory Committee, comprising members both inside and outside the academic medical center, with expertise in medicine, industry, manufacturing, and other disciplines, allows for the prioritization of projects. Finally, the home institution financially supported the overhead for the cGMP facility. Individual investigators provide the funding for clinical studies, whereas the institution provides additional matching support for manufacturing. The facility and its governance and management structures have remained solvent for more than 10 years.

Our own institution, the Mayo Clinic College of Medicine and Science, collaborated with their affiliated hospitals and the Mayo Clinic Cancer Center to establish the HCTL in 1998. These cGMP facilities enable multiple investigators across the Mayo system to share manufacturing costs and avoid duplicative efforts. The 57,000 square foot HCTL occupies three floors. One of these three floors contains the cGMP facility utilized for manufacture; the other two floors house additional research space utilized by investigators to develop potential products to be manufactured on the cGMP facility floor. Investigators using this space are typically clinician-scientists making the translational step from bench to bedside. The majority of the work conducted in this cGMP facility serves the three associated entities mentioned above: Mayo Clinic College of Medicine and Science, Mayo Clinic Cancer Center, and Mayo Health Care System. However, this cGMP facility also performs contract manufacturing for other major academic and research medical centers.

Several key components of the Mayo HCTL were identified that would be transferrable to a Mayo Biomaterials and Biomolecules cGMP facility. First, the physical proximity of the manufacturing facility to the clinic supports accelerated translation to first-in-human studies and subsequent clinical trials. Second, although the majority of the Center's work is internal and nonbillable, the ability to serve as a contract manufacturer for other academic medical institutions generates income to maintain the facility. Finally, hiring dedicated cGMP-trained staff, shared by various investigative teams, is critical to successfully manufacturing therapeutic products.

Although we were able to learn from our sister facility, it was important to have two separate facilities for the manufacture of biomaterial and cellular products, because of differences in requirements for the facilities, including structural components such as heating, ventilation and air conditioning systems and environmental monitoring, and to avoid cross-contamination of biologic with nonbiologic materials. A challenge yet to be addressed because of the early stage of the biomaterials facility is how best to coordinate use of components manufactured in both facilities for combination products; this is something our team hopes to address in the near future.

Based on the lessons learned, the team at the Mayo Clinic decided to construct a pilot facility with a larger facility as a long-term goal. This would allow development of a working model with a relatively small initial capital investment.

Clean Room Design in an Academic Medical Center

The first priority for the team was to identify an architectural engineering company with expertise in cGMP facility design. The next major challenge was to identify an existing location on campus that would be appropriate to convert into a biomaterials-focused cGMP manufacturing facility. The space needed had to meet two key requirements: air handling and access. Although these may seem like relatively simple requirements, they posed unique challenges to our team as we attempted to identify space that could be appropriately retrofitted to accommodate these requirements.

The first requirement was that compliance of air flow requirements for the clean rooms used for manufacturing medical devices could be achieved. The air flow system needs to simultaneously accommodate both fume hood and clean room requirements. It is important to note that International Standards Organization (ISO) and cGMP standards for air handling vary based on the type of product being manufactured and what components will be handled within that facility. The air handling system in the existing HCTL facility was not compatible with the air handling requirements for the proposed Biomaterials and Biomolecules facility. Air handling for a cell manufacturing facility involves recycling a significant proportion of the filtered air within the facility system. This contrasts with a materials facility that may use explosive or combustible organic solvents. This requires a separate air handling system to be constructed for the Biomaterials and Biomolecules cGMP facility to intake outside air, filter it to cGMP standards, and vent it back outside, in addition to having the standard air flow system that serviced fume hoods.

The second requirement was controlling access to the facility. Only authorized personnel would be allowed to enter the facility. This was achieved by using a card access security system, thus monitoring the entry and exit of authorized personnel.

It was decided early in the architectural process to have a two-component design. The first component would be a shell that provides an outer limit of controlled access and an internal clean air environment to ISO 8 air quality (<100,000 particles/m³). Within this would be a second area for manufacturing housed within an ISO 7 modular, free-standing clean room with its own high energy particulate air filtering system.

Making the Most of 1000 Square Feet

These considerations resulted in an ∼1000 square feet facility located in a research building on the Mayo Clinic Rochester campus. The facility is divided into several spaces including a gowning room, a cylinder closet for storage of gases for chemical synthesis, a materials airlock to facilitate clean handling of incoming raw materials and finished products, and a de-gowning room (Fig. 1). The clean room space encompasses a 452 square feet “Synthesis Lab” for chemical synthesis activities, with a 130 square feet free-standing ISO 7/CL 10,000 prefabricated clean room (the “Fabrication Room”) located within the Synthesis Lab. The fabrication room contains an ISO 6 laminar flow biological safety cabinet for final product assembly.

FIG. 1.

Floor plan of the 1000 square feet biomaterials and biomolecules current good manufacturing practice facility, part of the Mayo Clinic Center for Regenerative Medicine (Rochester, MN). The area outlined within the green dotted lines is the “Synthesis Lab” with ISO 8 air particle specification (<100,000 particles/m³) for chemical synthesis activities; the area within the purple dotted lines is the free-standing ISO 7 (<10,000 particles/m³) modular “Fabrication Room”; the area within red dotted lines is an ISO 6 (<1000 particles/m³) laminar flow biological safety cabinet for final product assembly. ISO, International Standards Organization.

To maximize the facility's ability to accommodate a broad array of techniques and processes, it is outfitted with equipment to support chemical synthesis for the manufacture of polymeric biomaterials. The facility has dedicated equipment that includes a biological safety cabinet, a fume hood, an airborne particle counter, microbial air samplers, a gravity convection oven, rotary evaporator, and a refrigerator and freezer. Also present in the fume hood is a full Schlenk line setup that allows inert gas reaction techniques to be utilized during polymer synthesis. The equipment shared here was selected for inclusion in our cGMP space based on the specific manufacturing projects currently underway, and is meant to be an illustration of what may be included. The facility was designed so that additional equipment may be incorporated on a case-by-case basis to support future manufacturing projects.

Regulatory and Quality Considerations

As at most academic medical centers, processes for clinical trials and development of medical products are well-established at the Mayo Clinic. Manufacturing medical products, however, is relatively unusual in part because of the physical space and its requirements (as noted above) as well as the substantial regulatory hurdles.

The FDA incorporated the cGMP requirements for medical devices into a quality system regulation found in Code of Federal Regulations (CFR) Title 21 Part 820 (21 CFR 820). (https://fda.gov/medicaldevices/deviceregulationandguidance/postmarketrequirements/qualitysystemsregulations/default.htm). The quality system regulation includes requirements related to the methods used in, and the facilities and controls used for, designing, manufacturing, packaging, labeling, storing, installing, and servicing of medical devices intended for human use. Quality system requirements pertinent to management responsibility (21 CFR 820.20), personnel (21 CFR 820.25), design controls (21 CFR 820.30), document controls (21 CFR 820.40), purchasing controls (21 CFR 820.50), production and process controls (21 CFR 820.70), labeling (21 CFR 820.120) and packaging (21 CFR 820.130) controls, storage (21 CFR 820.150) and distribution (21 CFR 820.160), records (21 CFR 820.180), and so on, can be found under the respective sections of Code of Federal Regulations Title 21, Part 820. Manufacturing must comply with federal regulations, standards, and practices.

Shifting from a “practice of medicine” to a “good manufacturing practices” concept in an academic research setting is challenging, as the culture and methods of clinical research differ from those used in industry and contract manufacturing. Four key concepts have been identified based on the experience of developing the facility described above, and should be communicated to investigators and staff working in an academic medical center cGMP facility: (i) an independent quality management system (the quality system personnel report through the Mayo Compliance Department, not to the facility directors or to the investigators' departments); (ii) establishment of and adherence to specific standard operating procedures; (iii) carefully and consistently documented work; and (iv) regular and appropriate risk/harm analysis and appropriate remedial action, when applicable.

Although this creates the foundation for establishing a quality system, these concepts are sometimes in conflict with the culture of biomedical research in an academic setting. Communicating the critical nature of these concepts to your stakeholders is imperative so they can integrate them as part of the “culture” that is critical to the success of an academic cGMP facility. One successfully documented method is to relay these concepts through the lens of patient safety. Another approach is to provide proven evidence that a quality system for product manufacturing is a “bench to bedside” safety approach for patients and therefore compliant with FDA standards.

FDA regulations with respect to cGMPs are constantly evolving. The field of regulatory science is addressing development of novel regenerative medicine products that will involve combinations of materials, cells, and biological products. We believe that developing an integrated quality management system will facilitate more rapid translation. We are currently building such an integrated system that will allow combination of products from different facilities within the institution with minimal barriers.

Conclusions

In an effort to support an investigator's ability to have continued oversight of their projects as they move their work from the laboratory into first-in-human safety studies, the Mayo Clinic's CRM established the cGMP Biomaterials and Biomolecules Facility. In addition, we are working on identifying the most effective way to communicate manufacturing and quality concepts to our Mayo researchers and clinicians. This is an ongoing process and must be tailored to the individual teams the facility supports.

Important take-home messages:

It is feasible to establish a dedicated biomaterials cGMP facility within an academic medical center by retrofitting an existing space to meet air handling and environment control requirements.

A two-component clean room design with an ISO 8 outer area and an ISO 7 modular inner area offers the flexibility of bringing in more than one product on a relatively small footprint.

An independent quality management system is the key to regulatory compliance and hence the validity of the facility.

Shifting from a “practice of medicine” to a “good manufacturing practices” concept in an academic research setting is challenging. It is essential that all GMP personnel are trained accordingly and that roles and responsibilities are defined.

The purpose of our Biomaterials Facility was to create institutional knowledge and resources to decrease the time it takes to translate novel discoveries from research to clinical trials.

Although unforeseen challenges still exist in this process, each product that we have encountered to date has had a different translational and regulatory pathway. Maintaining a balance between following protocols and establishing quality as part of the culture is both necessary and critical to the future success of any cGMP facility associated with an academic medical center.

Footnotes

Acknowledgment

The authors acknowledge the Mayo Clinic Center for Regenerative Medicine for funding and support of the creation and operation of this cGMP Biomaterials and Biomolecules Facility.

Disclosure Statement

No competing financial interests exist.

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