By: Stephen M. Hahn, M.D., Commissioner of Food and Drugs, and Anand Shah, M.D., Deputy Commissioner for Medical and Scientific Affairs
Americans may be surprised to learn that many 21st century medical products are still being manufactured using technologies commonly employed since the middle of the last century. These manufacturing platforms are not dynamic and can increase the risk of shortages, limit flexibility during an emergency, and contribute to the high cost of medical products. For the past several years, the U.S. Food and Drug Administration has sought to encourage and facilitate the adoption of “advanced manufacturing,” which refers to new and emerging approaches for the production of medical technologies.
Advanced manufacturing approaches are applicable to different medical product areas. For example, process intensification methods, such as continuous manufacturing, can simplify and centralize the production of many essential medicines. Likewise, techniques such as 3D printing can help produce patient-specific medical devices. Furthermore, digital and smart design and manufacturing processes also promise to increase efficiency and reduce uncertainty.
The potential public health value of advanced manufacturing is even greater in the context of the ongoing COVID-19 pandemic, which has highlighted the strain on supply chains and the need for adaptive manufacturing systems to accelerate the production of medical countermeasures. The FDA has established a strong regulatory foundation to support the uptake of advanced manufacturing, and COVID-19 provides the unique impetus to spur further advancement of medical manufacturing.
Agency-Wide Support for Advanced Manufacturing
FDA regulations cover both sides of the innovation equation: development (whether the product meets the appropriate statutory standard) and manufacturing (whether quality products can be produced for widespread use). Many manufacturers continue to use the same production techniques that were developed more than 50 years ago. Typical manufacturing processes that use long shipping lines or outsourced supply chains render U.S. manufacturing vulnerable to delays, disruptions, and quality control issues. These existing supply chain vulnerabilities have been exacerbated during the COVID-19 pandemic. Additionally, batch manufacturing lacks the flexibility needed to sustainably produce therapies for the personalized medicine era; this is a significant concern given that the FDA anticipates approving approximately 40 gene therapies in the next few years.
Advanced manufacturing often enables innovation, increases in efficiency, and improved supply chain resiliency for medical products that provide wide-ranging public health benefits. Over the past decade, the FDA made strategic, forward-looking investments in personnel, policies, and processes to create a clear regulatory pathway for innovators across the three medical product areas of drugs, biologics, and devices.
First, the agency recognized that innovators seeking to adopt advanced manufacturing technologies may be concerned about the technical and regulatory challenges associated with transitioning away from their existing platforms. To this end, the FDA’s Center for Drug Evaluation and Research (CDER) created the Emerging Technology Program, which has a dedicated team available to provide pre-submission support on issues such as the development of process control measures for continuous manufacturing of drugs. To provide focused expertise for advanced manufacturing of biological products, the FDA’s Center for Biologics Evaluation and Research (CBER) established the Advanced Technologies Team, which works with prospective developers on issues such as technical considerations for platform technologies in gene therapy.
Second, the FDA recognizes that policy must keep pace with innovation. To expedite the development of newer technologies, the agency developed a series of “leapfrog” guidance documents, which the FDA uses to share initial thoughts regarding emerging technologies that are likely to be of public health importance. Such “leapfrog” guidance documents include the FDA’s Center for Devices and Radiological Health’s (CDRH) 2017 guidance on “Technical Considerations for Additive Manufactured Medical Devices,” which encompasses many technologies including 3D printing. The agency has provided further regulatory clarity as technologies mature and are commercialized; for example CDER issued guidance in 2019 on “Quality Considerations for Continuous Manufacturing.” The FDA’s engagement in public dialogue supports the proactive identification and resolution of potential barriers for the transition to advanced manufacturing.
Third, as a science-based agency, the FDA supports research and partnerships that expand the knowledge base for advanced manufacturing. For example, the FDA has used authorities in the 21st Century Cures Act to award research grants to support investigators exploring key questions around monitoring and control techniques for advanced manufacturing platforms. To foster collaborations across the public, private, and non-profit sector, the FDA’s Office of the Chief Scientist (OCS) launched a new program for advancing regulatory science in public health and formed partnerships with stakeholders such as America Makes, BioFab USA, the National Institute for Innovation in Manufacturing Biopharmaceuticals (NIIMBL), and a number of industry organizations and clinical societies. OCS has also spearheaded multiple intramural research programs to help develop the regulatory expertise required to evaluate advanced manufacturing technologies. These initiatives will enable the FDA to identify and address cross-cutting scientific, technical, and regulatory challenges and opportunities for advanced manufacturing.
Modernizing Manufacturing is Key to All-Hazards Preparedness
The COVID-19 pandemic has shown how conventional manufacturing practices and predominantly international supply chains may be a liability for America’s emergency response efforts. In addition to the policy and programmatic foundations described above, the FDA has also taken a number of actions to shore up manufacturing capacity specifically for public health preparedness. For example, CDER entered a multi-year partnership with BARDA, the Biomedical Advanced Research and Development Authority, to explore how continuous manufacturing techniques could improve America’s capacity to rapidly manufacture medical countermeasures during emergency situations. During COVID-19 specifically, OCS and CDRH helped develop a Memorandum of Understanding between the FDA, the National Institutes of Health, and the Department of Veterans Affairs to facilitate information sharing on 3D printing to help support manufacturing of essential medical supplies such as personal protective equipment and medical device parts.
Advances in regulatory science are not an end in themselves. True public health preparedness requires incentives and investments in the technologies that the agency has been promoting for years. Increasing emphasis on domestic manufacturing strengthens our response capability, yet it is not enough to bring supply chains back home. We must also ensure that the renewed focus on the importance of domestic manufacturing capacity is paired with a recognition of the capital requirements and scientific expertise needed to adopt more resilient and efficient platforms.
The FDA is committed to doing its part to foster the adoption of advanced manufacturing technologies. To reduce the burden on innovators, the agency is actively working to ensure international concordance on guidelines for continuous manufacturing as part of the International Council for Harmonisation’s Q13 proposal. To ensure that best practices are informed by the latest research, the agency is committed to monitoring ongoing grant programs, with the intent of fostering initiatives that can demonstrate tangible improvements in safety, quality, and efficiency. To promote communication about the adoption of best practices and innovative ideas between stakeholders, the FDA will continue to proactively provide forums for scientific discussion, participate in national and international workshops, and collaboratively engage stakeholders.
Because pandemics by nature are unpredictable, our approach to manufacturing must be adaptable. Advanced manufacturing provides an approach for protecting our supply chain and improving our response capacity during crisis situations. By establishing the regulatory foundation, the FDA has created a pathway for industry to continue adopting the needed improvements in manufacturing technology for the benefit of public health.