By Madeleine Giaquinto, JD, and Kalah Auchincloss, JD, MPH
According to the FDA, “advanced manufacturing” is a collective term for new technologies that can “improve drug quality, address shortages of medicines, and speed time-to-market.” Generally, advanced methods either employ cutting-edge new technology (e.g., 3D printing) or use established techniques in a new or unique way or in a new domain (e.g., continuous manufacturing).1
The COVID-19 pandemic created a heightened sense of urgency around preexisting supply chain vulnerabilities — perhaps one silver lining to this has been broader government efforts to further break down barriers to the adoption of advanced manufacturing. These efforts include introduction of H.R. 4369, the National Centers of Excellence in Advanced and Continuous Pharmaceutical Manufacturing Act of 2021,2 (which aligns with creation of a White House task force dedicated to strengthening critical supply chains, including pharmaceutical manufacturing3), and the FDA’s new regulatory framework for the review and approval of products manufactured using novel technologies — FRAME.4 Additionally, the agency has engaged with external academic institutions on a range of other research topics to further enhance innovation and understanding around the public health promise of these technologies.5
Precedent for FDA approval of products manufactured using advanced technologies flowed from the agency’s long-standing efforts to modernize pharmaceutical supply chains for greater quality assurance. Now, new support from Capitol Hill and the White House, combined with new FDA regulatory efforts and added external stakeholder collaboration, may mean a new pharmaceutical manufacturing model is well underway.
H.R. 4369 & FDA
The pandemic exposed and exacerbated preexisting supply chain vulnerabilities that were causing quality deficiencies and leading to drug shortages. This presented the need for broader government alignment in supporting development of advanced manufacturing technologies that have demonstrated value in improving quality and mitigating shortages.
On Oct. 19, 2021, the House passed H.R. 4369. The bill authorizes $100 million over four years to establish National Centers of Excellence in Advanced and Continuous Manufacturing at U.S. academic institutions.6 It grants FDA the authority to designate National Centers of Excellence based on certain criteria, such as research and developmental capabilities of the institution; “scalable” manufacturing knowledge-sharing networks; demonstrated experience in designing new technologies; and a history of successful knowledge transfer.7 The new bill builds on existing partnerships between FDA and research institutions, such as Rutgers University’s Center for Structured Organic Particulate Systems (C-SOPS), which has been a player in the advancement and integration of continuous manufacturing technologies into commercial production.8
The House Energy and Commerce Committee stated that the goal of this initiative is to create opportunities for engagement between FDA and stakeholders “to craft a national framework for advanced and continuous manufacturing, including workforce development, standardization, and collaboration with manufacturers.”9 Through these partnerships, FDA will be able to leverage data on best practices to develop a road map for the advancement of continuous manufacturing and industry’s adoption of these technologies.
Developing A New Regulatory Framework
To operationally prepare for the promising impact of H.R. 4369 and anticipated innovation in this space, FDA recently initiated new efforts to address identified regulatory hurdles through development of a new regulatory framework for advanced manufacturing technologies, called the Framework for Advanced Manufacturing Evaluation (FRAME).10
FRAME is focused on four categories of manufacturing technology that are expected to be in use within the next decade: end-to-end continuous manufacturing, distributed manufacturing, point-of-care (POC) manufacturing, and use of artificial intelligence (AI) and machine learning (ML) in manufacturing processes. FDA’s Office of Pharmaceutical Quality (OPQ) is undertaking a phased approach in its development of FRAME, with the first phase focused on evaluating existing regulatory frameworks for gaps; the second phase focused on planning implementation of FRAME and assessing the impact of regulatory changes on product approvals; and the third phase focused on seeking public input to eliminate hurdles and harmonize regulations internationally.
The third phase of FRAME was initiated with release of FDA’s draft guidance, Q13 Continuous Manufacturing of Drug Substances and Drug Products, for public comment in October 202111 and will continue with other public outreach efforts, including a series of forthcoming white papers that will also be made available for public comment.12 Over the course of this “multi-year effort,”13 FDA will use feedback received through public outreach, coupled with data generated by research partners established under H.R. 4369, to further inform its thinking, eliminate hurdles, clarify expectations, begin to implement different components of its regulatory framework, and work to harmonize regulations internationally.
The first and second phases of FRAME involved, respectively, FDA’s work with the National Academies of Sciences, Engineering, and Medicine (NASEM) to identify technical and regulatory hurdles (discussed further below), and the establishment of an internal Center for Advancement of Manufacturing Pharmaceuticals and Biopharmaceuticals. The intent of the internal center is to improve collaboration between CDER and CBER and ensure coordination on science and policy matters that affect both centers.14 When it comes to revising regulations, such as those governing review and approval of new products, CDER and CBER’s coordination of changes is important to prevent an adverse impact on other parts of the agency that are still relying on existing regulations.
FDA’s Long-standing Support Of Advanced Manufacturing
The desire to modernize pharmaceutical production processes has existed at FDA for nearly two decades.15 The agency’s early efforts centered on transitioning to a risk-based quality management framework involving more controlled and streamlined pharmaceutical production processes.16 Pursuant to this vision, the agency engaged in a two-years-long initiative to evaluate its regulatory programs, in part to encourage the adoption of new technologies and quality management techniques across all aspects of pharmaceutical production.17
More recently, FDA established teams to facilitate engagement between the agency and companies interested in producing products using innovative technologies, such as CDER’s Emerging Technology Program (ETP), established in 2014 (upgraded to ETP 2.0 in 2021), and CBER’s Advanced Technology Team (CATT), established in 2019. The ETP and CATT provide opportunities to identify, discuss, and resolve technical and regulatory issues related to advanced manufacturing prior to submission of an application. FDA began approving products manufactured using innovative technologies in 2015 and has approved at least 12 such products to date, but there are still hurdles that prevent widespread industry adoption of advanced manufacturing technologies.18
Identifying Regulatory Hurdles
Since FDA’s initial efforts to support continuous manufacturing processes, rapid innovation in more advanced technologies has occurred. While demonstrating the potential for significant public health benefit, this rapid innovation has also created various regulatory and technical challenges that hinder wider industry adoption of such technologies.
At a June 2020 NASEM workshop, CDER-OPQ Director Michael Kopcha, Ph.D., Rh.P., explained that current regulatory requirements that were developed based on conventional batch processing “do not translate well into new manufacturing technologies that allow for varied batch sizes, inline analytics, and higher-fidelity methods for detecting batch-to-batch variation.”19 Subsequently in March 2021, NASEM published a consensus report, which was funded by FDA, outlining technical and regulatory challenges and offering potential solutions for overcoming them.20 Among a range of regulatory and technical gaps identified, the report highlighted the need for more fluid and targeted guidance; a focus on technology as opposed to individual product approvals; additional mechanisms for industry input and collaboration (including feedback on guidance); and an expanded scope of the ETP.21 These findings helped inform FDA’s development of FRAME and its new draft guidance on continuous manufacturing, as discussed above.
Strategizing Based on Industry Feedback and Lessons Learned
Industry will have additional opportunity to provide feedback on barriers to adoption and submission strategies at a future public workshop as well. This workshop will be hosted by FDA by the end of FY2023 as part of announced PDUFA VII commitments.22 A public comment period will follow the workshop, after which FDA will issue a draft strategy document outlining specific actions needed to further facilitate and break down barriers to the adoption of innovative manufacturing technologies. The workshop will aim to address best practices and lessons learned from the ETP and CATT programs; industry-presented case studies on previous submissions; barriers and regulatory strategies for adoption and implementation of innovative technologies; and science- and risk-based approaches for assessing innovative technologies across platform products.23
Building a Stronger Workforce
In addition to developing a regulatory framework to accommodate products manufactured using novel technologies, FDA is also working to enhance its capacity and capability to handle review and approval of products manufactured using new technologies. In an October 2021 FDA Voices blog post, Kopcha and CDER Director Patrizia Cavazzoni, M.D., discussed plans to create “ETP 2.0 to meet workload challenges and enhance communication with companies” through a greater degree of personnel training on new technologies, “[improving] our ability to evaluate them.”24 As discussed above, the ETP was established to facilitate the adoption of innovative approaches to pharmaceutical design and production. Since its inception and through 2020, the ETP held over 100 meetings and approved 12 regulatory applications.25 As highlighted by NASEM in its 2021 Consensus Report, the limited capacity of the ETP has been seen as a regulatory hurdle, and a program scale up may be required. As a result, FDA proposed an expanded program that will focus, in part, on gaining institutional experience with novel technologies and harnessing this knowledge through skills development and workforce training.
Furthering Research and Understanding
FDA is also engaging with academic research institutions to deepen its understanding of how novel technologies can be leveraged to optimize its oversight capabilities and further strengthen pharmaceutical quality throughout supply chains. In recent months, both CDER26 and CBER27 have announced the launch of research initiatives on a range of topics related to integration, application, assessment, and understanding of advanced manufacturing technologies; this includes various grants aimed at enhancing innovation for the manufacturing of vaccines against emerging infectious disease and rare diseases, as well as use of data analytics for biomanufacturing and other assessment tools to ensure product quality.
FDA has long sought to promote the modernization of pharmaceutical manufacturing by encouraging industry’s implementation of novel technologies that provide greater quality assurance along supply chains and mitigate risks of drug shortages. Despite these efforts, regulatory and technical barriers have been an impediment to widespread adoption of these technologies. Passage of H.R. 4369 aligns with FDA initiatives, including FRAME, as well as the broader national strategy, to break down remaining barriers to adoption of advanced manufacturing, ultimately building more resilient pharmaceutical supply chains in the wake of COVID-19 and beyond.
About The Authors:
Madeleine Giaquinto is manager of regulatory affairs at Greenleaf Health, Inc. She provides clients with timely analysis of FDA regulations, policies, and guidance documents and strategic advice on FDA engagement regarding compliance-focused issues and good practice standards for FDA-regulated products. Giaquinto has worked in diverse settings across the life science field, including within legal, nonprofit, government affairs, and public health policy specialties, and has a robust set of skills and knowledge of each as they intersect with regulatory compliance and federal and state healthcare policy matters. She has a B.S. in biology from Georgetown University and a J.D. from George Mason University School of Law. You can connect with her on LinkedIn.
Kalah Auchincloss, J.D., M.P.H., is executive vice president of regulatory compliance and deputy general counsel for Greenleaf Health. She has more than a decade of food and drug legal, policy, and regulatory experience at the FDA, on Capitol Hill, and in the private sector. At Greenleaf, Auchincloss advises pharmaceutical and medical device companies on compliance, policy, and other issues. Before moving to Greenleaf, Auchincloss spent six years at the FDA, most recently as deputy chief of staff, but also serving in CDER’s Office of Compliance and Office of Regulatory Policy. You can contact her at firstname.lastname@example.org
- FDA Webpage on Advanced Manufacturing, https://www.fda.gov/emergency-preparedness-and-response/mcm-issues/advanced-manufacturing#whatisadvancedmanufacturing.
- H.R. 4369, National Centers of Excellence in Advanced and Continuous Pharmaceutical Manufacturing Act (October 2021), available at https://energycommerce.house.gov/sites/democrats.energycommerce.house.gov/files/documents/
- The White House Briefing Room, “Biden-Harris Administration Announces Supply Chain Disruptions Task Force to Address Short-Term Supply Chain Discontinuities” (June 2021), available at https://www.whitehouse.gov/briefing-room/statements-releases/2021/06/08/fact-sheet-biden-harris-administration-announces-supply-chain-disruptions-task-force-to-address-short-term-supply-chain-discontinuities/.
- FDA Voices, “FDA’s Advanced Manufacturing Initiatives Helping to Provide Quality Human Drugs for Patients,” (October 2021), available at https://www.fda.gov/news-events/fda-voices/fdas-advanced-manufacturing-initiatives-helping-provide-quality-human-drugs-patients.
- FDA, “Advanced Manufacturing: Funding Updates,” (October 2021) available at https://www.fda.gov/emergency-preparedness-and-response/mcm-issues/advanced-manufacturing#fundingupdates.
- See, supra at n.3.
- Press Release, “Pallone’s Bill to Support Advanced and Continuous Pharmaceutical Manufacturing Passes in the House,” (October 2021), available at https://pallone.house.gov/media/press-releases/pallone-s-bill-support-advanced-and-continuous-pharmaceutical-manufacturing.
- House Committee on Energy & Commerce Press Release, “Pallone and Eschoo Praise House Passage of Four Public Health Bills,” (October 2021), available at https://energycommerce.house.gov/newsroom/press-releases/pallone-and-eshoo-praise-house-passage-of-four-public-health-bills.
- SBIA Pharmaceutical Quality Symposium, Adam Fisher, “Addressing the Advanced Manufacturing Regulatory Framework” (October 201), available at https://www.fda.gov/drugs/news-events-human-drugs/pharmaceutical-quality-symposium-2021-innovations-changing-world-10262021-10272021.
- FDA Draft Guidance, “Q13 Continuous Manufacturing of Drug Substances and Drug Products,” (October 2021), available at https://www.fda.gov/regulatory-information/search-fda-guidance-documents/q13-continuous-manufacturing-drug-substances-and-drug-products.
- See, supra at n.13.
- See, supra at n.5.
- FDA Initiative – Final Report, “Pharmaceutical CGMPs for the 21st Century: A Risk-Based Approach” (September 2004), available at https://www.fda.gov/media/77391/download.
- See, supra at n.2.
- NASEM Workshop: Proceedings in Brief, “Barriers to Innovations in Pharmaceutical Manufacturing” (September 2020), available at https://www.nap.edu/read/25907/chapter/1.
- NASEM Consensus Study Report, “Innovations in Pharmaceutical Manufacturing on the Horizon” (March 2021), available at https://www.nap.edu/resource/26009/FDA%20Pharma%204-pager.pdf.
- FDA, “PDUFA Reauthorization Performance Goals and Procedures Fiscal Years 2021 Through 2027,” p. 52, available at https://www.fda.gov/drugs/news-events-human-drugs/pharmaceutical-quality-symposium-2021-innovations-changing-world-10262021-10272021.
- See, supra at n.5.
- See, supra at n.2.
- See, supra at n.6.
- FDA, “CBER Advanced Technologies Program Extramural Research Funding” (September 2021), available at https://www.fda.gov/emergency-preparedness-and-response/mcm-issues/advanced-manufacturing#fundingupdates.