Two US senators have directed a letter to the FDA Commissioner to promote domestic pharmaceutical supply chain resilience through the implementation of programs to manufacture drugs and APIs using advanced manufacturing technologies.

By Patriica Van Arnum, Editorial Director, DCAT, pvanarnum@dcat.org

Calling for FDA action
Earlier this week (September 17, 2024), US Senators Marco Rubio (R-FL) and Angus King (I-ME) sent a letter to the US Food and Drug Administration (FDA) Commissioner Robert Califf urging the agency to set clear standards and industry guidance for adopting advanced manufacturing technologies (AMTs) in order to strengthen the US domestic pharmaceutical supply chain.

“As the FDA works toward finalizing its Advanced Manufacturing Technology Designation Program and continues to evaluate and approve AMTs {advanced manufacturing technologies} for commercial use, we urge you to ensure that these efforts prioritize domestic supply chain resilience and enforce clear guidelines for manufacturers to take part in this program,” said the senators in their letter to FDA.

Earlier this year (February 2024), FDA issued draft guidance, Advanced Manufacturing Technologies Designation Program, to provide recommendations to persons and organizations interested in participating in FDA’s Advanced Manufacturing Technologies Designation Program, which is intended to facilitate the development of drugs, including biological products, manufactured using an AMT that has been designated as such under the program. In issuing the draft guidance, FDA said that these technologies can be integral to ensuring quality and supporting a robust supply of drugs of critical importance, noting that AMTs can directly improve product quality through higher capability manufacturing designs and enhanced controls (e.g., leading to fewer human errors). They can also play a role in mitigating drug shortages by facilitating US-based drug supply. FDA provided a comment period through March 13, 2024, to gain feedback on the draft guidance from the industry and interested stakeholders.

Although acknowledging FDA’s work to advance ATMs, such as continuous manufacturing of active pharmaceutical ingredients (APIs), Senators Rubio and King in are calling on FDA to move forward on issuing its final guidance on ATMs. “We commend the FDA’s work to issue industry guidance for considerations specific to continuous manufacturing of APIs, but greater action is needed to promote a resilient domestic API supply chain,” they said in their letter to FDA. “We are concerned that the FDA has not yet created a feasible pathway for stakeholders to invest confidently in domestic AMTs. As the FDA continues to evaluate its AMT regulations, we urge you to prioritize domestic manufacturing facilities and commit to frequent engagement with industry and patient stakeholders, ensuring a clear and efficient approval process for AMTs and their products.”

Senators Rubio and King are calling for FDA to issue its final guidance as they say AMTs are an important component to lower the cost of US-based drug manufacturing and facilitate the reshoring of key APIs domestically in the US. “AMTs, such as continuous manufacturing sites, provide a promising pathway to lower the cost of domestic drug manufacturing, and accelerate the reshoring of key API production here in the United States,” the senators said in their letter. “Yet, the FDA has not yet invested sufficient resources toward developing clear regulatory guidelines for these innovative manufacturing tools. The FDA must quickly finalize and implement the AMT Designation Program, as directed by Congress, to provide companies regulatory clarity as they evaluate whether to invest and seek approval of AMTs for their products.”

Seeking answers to eight questions on the ATM guidance
In their letter, the senators put forth a request to FDA to answer eight questions regarding the agency’s final guidance on its Advanced Manufacturing Technologies Designation Program. These questions are outlined below.

1. What strategies has the FDA implemented to encourage greater investment by domestic drug manufacturers into AMTs, such as continuous manufacturing? How has the FDA engaged with industry to further refine its regulations and expand opportunities for approval?
2. How is the FDA ensuring that the AMT Designation program will benefit more domestic manufacturing facilities than foreign-based facilities?
3. Based on the current application pool for AMTs seeking FDA approval through currently active pathways, what is the ratio of domestic versus foreign-based facility applications that the FDA has received? What is the ratio of domestic versus foreign based facilities that have been approved?
4. Has the FDA received any new continuous manufacturing applications for generics, especially among pharmaceuticals experiencing domestic shortages? Will the FDA consider a drug or API’s risk for shortage when evaluating applications for the AMT Designation program?
5. How is the FDA communicating about the AMT Designation Program to eligible entities and the public? How is the FDA ensuring the drug manufacturers of all sizes are aware of the program and understand the requirements to apply?
6. How is the FDA ensuring the timely approval of continuous manufacturing technologies?
7. Has the FDA seen continued growth in the number of approved continuous manufacturing products since 2022?
8. What is the implementation status of the AMT Designation Program? Has the FDA made progress on implementing the required program since the draft guidance period, which closed on March 13, 2024? Has the program accepted any designation requests for new technologies?

Providing the case for FDA action
In seeking answers to these questions, Senators Rubio and King said that although FDA has identified current regulatory barriers that are preventing more companies from adopting AMTs in their manufacturing pipelines, “we are concerned that the FDA has not addressed these barriers adequately.” In their letter to FDA, they cite a 2021 report by the National Academies of Science, Engineering, and Medicine that identified regulatory challenges to implementing advanced manufacturing for drugs, which included challenges within FDA’s approval process for each step in the manufacturing process and the lack of guidance and expertise within FDA related to advanced manufacturing technologies.

“Industry stakeholders must be able to establish the business case for the use of an AMT, but current ambiguities in the regulatory environment exacerbate challenges for arguing the business incentives for AMTs, deterring investment in these technologies,”  Senators Rubio and King said in their letter to FDA. They cited a 2023 report by the US General Accountability Office that found that only a few drugs manufactured using an AMT are currently approved for marketing in the US, noting that between 2015 and 2022, FDA had only approved 16 out of the 112 applications or supplemental applications that used an AMT. “This low rate of approval does not inspire investor confidence and proves that the FDA has considerable work to do to improve the regulatory environment for AMTs,” they said in their letter.