FDA program to lower US onshoring barriers gets industry support

The Food and Drug Administration held a public meeting on Sept. 30 at its White Oak campus in Silver Spring, Maryland to get industry feedback on its proposed PreCheck program, designed to lower the regulatory burden on onshoring new pharmaceutical manufacturing facilities in the United States.

“We have some distinct vulnerabilities that have sort of crept into our pharmaceutical supply chain,” said George Tidmarsh, director of the FDA’s Center for Drug Evaluation and Research, in his remarks welcoming participants to Tuesday’s meeting. “For decades, pharmaceutical manufacturing has increasingly shifted overseas, mostly due to cost and regulation.”

According to Tidmarsh, more than half of all drugs distributed domestically are manufactured overseas, while most active pharmaceutical ingredient (API) production occurs in just a few countries. As a result, he said U.S. onshoring is a national imperative.

PreCheck, which was launched in August, is part of the FDA’s response to President Donald Trump’s Executive Order 14293 which calls for regulatory relief to promote domestic production of critical medicines. The agency’s program takes a two-phase approach to help facilitate new U.S. drug manufacturing facilities.

In PreCheck’s Facility Readiness Phase, companies will have increased opportunities for communication with FDA during site design and construction. The agency is encouraging the use of a Type V Drug Master File (DMF) to submit facility-specific quality and design information for future reference in application filings.

In PreCheck’s Application Submission Phase, manufacturers can participate in pre-application meetings and obtain early feedback from the agency to expedite development of the Chemistry, Manufacturing, and Controls (CMC) section of drug applications.

Tidmarsh in Tuesday’s meeting called the Facility Readiness Phase the “most urgent and immediate phase” in PreCheck, which is meant to provide manufacturers with more frequent communication with the FDA at critical development stages — including facility design, construction, and qualification.

“We want to make sure that manufacturers can speak clearly, openly, and early with FDA input,” Tidmarsh said. “The idea is not to wait until construction is well underway and design has happened. The idea is to talk now and make sure that we’re aligned so that when it comes to the final inspection and bringing the facility up there aren’t critical issues that could have been averted in the beginning.”

Regarding the Application Submission Phase in PreCheck, Tidmarsh commented that “early and often communication” between manufacturers and the FDA in pre-application meetings will help streamline development of the CMC section of the application.

“Early, frequent communication in all phases allows for a much more efficient process that I believe can lead to faster and probably less expensive onshoring of these facilities,” according to Tidmarsh. “Too often in the past it has been a one-way street and that’s the barrier we’re trying to break down.”    

Industry feedback

Among other areas, the FDA in Tuesday’s PreCheck meeting asked for industry input on what stakeholders consider the most significant regulatory hurdle in establishing new U.S. pharmaceutical manufacturing facilities.

Julia Edwards, senior vice president for global regulatory affairs-CMC and devices at Eli Lilly, said the drugmaker is “fully supportive and very excited” about the FDA’s PreCheck program. Edwards called out Lilly’s concerns about the “inflexibility and potential inconsistencies of the current inspection process” including the timing constraints, which could be alleviated by working earlier with the FDA under PreCheck.

Jeff Kinzer, vice president of CMC regulatory affairs-biologics at Johnson & Johnson, told the agency there is an “opportunity to build on the existing pre-operational review process.” Kinzer said pre-op review is a key element critical for success as “these facilities take many years to bring online” and there are long lead times for equipment.

“Being able to have a flexible framework — to have a conversation with FDA — will be very important in making sure that that’s efficient,” Kinzer said. “When that facility is ready to start transferring products in, we already know that we’re aligned with the agency.”             

Leerink Partners analysts in a Tuesday note to investors wrote that “while FDA officials acknowledged that initial implementation [of PreCheck] would be selective due to resource constraints and did not commit to any immediate changes/policy, FDA seemed receptive to feedback from industry stakeholders across large pharma and biotech, and there also appeared to be significant interest from the industry side on the implementation of such a program.”

Although industry participants in Tuesday’s meeting were “broadly supportive” of the direction of the agency’s PreCheck program, the analysts said stakeholders emphasized the need for flexibility and clarity in the proposed framework.

“Some key Issues/requests raised include PreCheck also applying to retrofitted modular expansions (vs. just greenfield sites), having a single FDA point of contact (vs. multiple), more flexible post-approval changes, reducing burden of PPQ batches and long stability timelines, easier scheduling of inspections, risk-based use of comparability protocols and greater leverage of prior knowledge (i.e., potential ‘surrogate’ inspections using a similar molecule or platform), decoupling inspections from application approval timelines, mechanisms for facility certification independent of any single product, reducing maintenance burden of Type V DMFs, clarity around what counts as sufficient facility readiness and how PreCheck would interact with global regulatory expectations (e.g., EMA, MRA partners),” the analysts wrote.

Going forward, the FDA will provide further guidance or rulemaking after gathering stakeholder input “with practical/broad impact still likely a year or more away,” according to the analysts.