FDA Programs to Support Advanced Manufacturing: Where Innovation Meets Regulation
In recent years, advanced manufacturing has gained traction in the pharmaceutical industry, transforming how drugs are developed, produced, and delivered. It is recognized, however, that there is a learning curve across the industry and FDA that is inherent to the development of such novel technologies. To prevent this learning curve from becoming a roadblock on the path to regulatory approval, the FDA has developed several collaborative programs to support advanced manufacturing. In this blog, we explore the concept of advanced manufacturing and outline the FDA programs that play a critical role in promoting innovation while ensuring product quality.
What is advanced manufacturing?
Advanced manufacturing refers to the use of innovative technologies to improve products or processes, often through automation, real-time monitoring, and data-driven quality control. In the pharmaceutical context, advanced manufacturing aims to improve drug quality, address shortages of medicines, and speed time-to-market through the use of innovative technologies like:
- Continuous manufacturing (CM): Traditional drug manufacturing is often performed in batch processes, where production is done in stages and halted between steps. Continuous manufacturing, by contrast, integrates all steps of drug production into a seamless, ongoing process.
- 3D printing (additive manufacturing): In the pharmaceutical sector, 3D printing allows for personalized medicine by creating precise dosages and unique drug delivery systems.
- Process analytical technology (PAT): PAT uses sensors and analytics to monitor critical quality attributes of a product during production, ensuring that it meets the required standards without the need for batch testing post-production.
- Automation and robotics: Automation, including the use of AI and robotics, allows for the consistent handling of materials, precise measurements, and controlled environments.
These techniques help to streamline production, reduce variability, and enhance the ability to produce personalized and complex medications.
How the FDA supports advanced manufacturing
As these advanced manufacturing technologies rapidly evolve, regulatory bodies play an essential role in ensuring their safe implementation. To accommodate the need for more flexible regulatory frameworks that meet the fast-paced innovation in pharmaceutical manufacturing, the FDA has developed many programs for sponsors to consider.
CDER Emerging Technology Program (ETP)
The FDA first established the Emerging Technology Program (ETP) in 2014, encouraging industry collaboration with select FDA staff. This collaboration was designed to address potential technical and regulatory challenges for novel technologies to facilitate the regulatory assessment of such technologies. The Emerging Technology Team (ETT) includes representatives from all relevant FDA pharmaceutical quality functions, e.g., the Office of Pharmaceutical Quality (OPQ), the Office of the Commissioner (OC), and the Office of Regulatory Affairs (ORA). The lifecycle of an ETP is illustrated in Figure 1 below.
Figure 1: Lifecycle of an ETP
To participate in an ETP, Sponsors must submit a Type C or pre-ANDA meeting request, as applicable, along with the additional requested information outlined in the Advancement of Emerging Technology Applications for Pharmaceutical Innovation and Modernization Guidance for Industry. Examples of technologies which have been accepted as an ETP include 3D printing manufacturing and continuous manufacturing processes. Benefits of an ETP include additional meetings between sponsors and the FDA (specifically, ETT members), site visits, as well as involvement of the ETT members in the quality assessment and inspections supporting the regulatory submissions.
CDER Framework for Regulatory Advanced Manufacturing Evaluation (FRAME) Initiative
As a result of the ETP, the FRAME initiative identified four advanced manufacturing technologies as priorities for CDER. With those specific innovations in mind, a regulatory framework for these advanced manufacturing technologies emerged.
Innovations under FRAME:
- End-to-end continuous manufacturing (E2E CM)
- Distributed manufacturing (DM)
- Distributed manufacturing units at non-traditional host sites
- Artificial Intelligence (AI)
This initiative has resulted in the publication of multiple discussion papers and action plans, as well as FDA workshops on these topics and the development of the ICH Q13 guidance on continuous manufacturing.
CBER Advanced Technologies Team (CATT)
Similar to CDER’s ETT, the CATT was established for collaborative discussions between CBER staff and sponsors of advanced manufacturing technologies in an effort to overcome potential technical and regulatory hurdles related to such novel technologies. Sponsors can leverage this program for early interactions with CBER staff, of particular importance for novel technologies. Also of note, the scope of the CATT is stated to include both manufacturing and analytical methods. To engage with the CATT, sponsors should submit their inquiries or meeting requests related to their advanced technology to: Industry.Biologics@fda.hhs.gov, and submissions should include the following elements:
- Note CATT in the subject line
- Maximum of two pages, including any figures or tables
- Brief description of the technology or product class
- Brief explanation of why it is substantially novel and unique
- Description of its impact in terms of improved biologic product manufacturing, characterization, quality, safety, or efficacy
- Summary of the manufacturing or development plan
- Any questions regarding perceived regulatory, technical, or other challenges for implementation
Innovative Technologies and Advanced Manufacturing Hub (I-TEAM Hub)
The FDA Office of Counterterrorism and Emerging Threats (OCET) has also established an advanced manufacturing program, with a focus on cross-cutting technologies – meaning those that incorporate two or more FDA-regulated product areas. One of the key facets of the OCET program is providing internal training opportunities to FDA staff, to build their expertise with the novel technologies. To support this, the Innovative Technologies and Advanced Manufacturing Hub (I-TEAM Hub) was created.
The I-TEAM Hub is a laboratory space specifically designed for FDA staff to have hands-on experience with various advanced technologies on which they would advise, e.g., AI/machine learning, 3D printing, etc. The I-Team Hub provides the FDA with facilities that foster learning – leading to a better understanding of the advanced technologies and, in turn, how best for FDA staff to evaluate them. From this, relevant guidance and policies may then be developed, including those from the center-specific innovation programs CDER Emerging Technology Program (ETP) and CBER Advanced Technologies Team (CATT).
Advanced Manufacturing Technologies Designation Program
The provision for the advanced manufacturing technologies designation program was enacted under the Food and Drug Omnibus Reform Act of 2022 (FDORA). As outlined earlier in this blog, innovative manufacturing techniques are key for producing superior quality medicine, as improvement in quality manufacturing can limit drug shortages due to quality-related issues. Innovation can also lead to faster time to market by accelerating drug development timelines, strengthening the supply chain, and providing better responsiveness during a public health emergency.
The process for an advanced manufacturing technologies designation is outlined below in Figure 2. It is highly recommended that a sponsor engage with the ETT or CATT prior to submitting an AMT designation request. To complete an AMT designation request, Sponsors should submit the request to: AMT_designation_requests@fda.hhs.gov, and include the following elements:
- Note REQUEST FOR AMT DESIGNATION in the subject line
- Provide requestor’s contact information, including name, address, email address, and telephone number for their main point of contact and indicate if the request is specific to CDER, CBER, or both
- Brief description of the method of manufacturing and why it should be considered for AMT designation
- Detailed description of how the method of manufacturing meets the eligibility criteria
- The context of use under which the proposed AMT will be used in drug development
- Regulatory, technical, or other challenges that the sponsor foresees with the proposed AMT
- Drug development timeline (as known) including planned submissions that would include the proposed AMT in the same context of use
- If applicable, information about previous engagement with ETT/CATT
Figure 2: AMT Designation Process
As highlighted with other AMT programs, a benefit to the AMT designation is the ability to have early and increased interactions with FDA staff – especially as they pertain to AMT technical and regulatory challenges.
While these programs can offer distinct advantages for sponsors who are developing advanced manufacturing technologies, a 2023 Government Accountability Office (GAO) study determined that regulatory challenges in this space persist and result in a level of uncertainty for sponsors. As a result, there has been a slow adoption of advanced manufacturing technologies by the industry, with only 16 approved applications or supplemental applications that incorporated an advanced manufacturing technology between 2015-late 2022 as reported in the GAO study. In the same period, 112 advanced technologies were accepted by CDER into the ETP. To address this, recommendations were made for program enhancements such as performance targets and associated timeframes against which the FDA might assess progress toward program goals.
With extensive experience in manufacturing techniques and regulations, the CMC services team at Premier Consulting can help sponsors navigate the development of advanced manufacturing technologies. Contact us today to find out how we can support your program.
References:
- https://www.fda.gov/about-fda/center-drug-evaluation-and-research-cder/emerging-technology-program-etp
- https://www.fda.gov/about-fda/center-drug-evaluation-and-research-cder/lifecycle-emerging-technology-program-etp
- https://www.fda.gov/vaccines-blood-biologics/industry-biologics/cber-advanced-technologies-team-catt
- https://www.fda.gov/emergency-preparedness-and-response/ocet-advanced-manufacturing/about-advanced-manufacturing-public-health-emergency-preparedness-and-response
- https://www.fda.gov/emergency-preparedness-and-response/ocet-advanced-manufacturing/innovative-technologies-and-advanced-manufacturing-hub-i-team-hub
- https://www.fda.gov/emergency-preparedness-and-response/mcm-issues/advanced-manufacturing
- Ranjani Prabhakara, Ph.D., CDER-D2S07-Prabhakara, REdI Annual Conference 2024, The Advanced Manufacturing Technologies Designation Program.
- FDA Guidance, Advanced Manufacturing Technologies Designation Program, December 2023, https://www.fda.gov/media/174651/download
- https://www.gao.gov/assets/gao-23-105650.pdf