Industry clamors for clarity on FDA’s advanced manufacturing designation program

Industry is welcoming of the US Food and Drug Administration's (FDA) upcoming advanced manufacturing technologies (AMT) program but is clamoring for more clarity on crucial details like what methods will be covered, which sponsors can take part, and how fast it would work.

The AMT program will foster and expedite the development of manufacturing methods that incorporate a novel technology or use an established technology in a unique way to produce a drug of equivalent or superior drug quality. FDA is required to create the program as part of Congress’ omnibus spending bill in December 2022. (RELATED: Omnibus brings new advanced manufacturing programs to FDA, Regulatory Focus 11 January 2023)

At the end of 2023, FDA outlined plans for the program, including application processes and communications, noting expectations for better quality, shorter development times, and more plentiful supply in draft guidance. The comment period for the guidance closed March 13, following a 30-day extension requested by some stakeholders. (RELATED: FDA guidance details new advanced manufacturing technology designation program, Regulatory Focus 14 December 2023)

“The general efforts of the FDA to encourage the early adoption of advanced manufacturing technologies (AMT) are welcome by industry, and this guidance could represent another element of this effort to enable faster launches and a robust supply chain through new manufacturing technology,” wrote the Biotechnology Innovation Organization (BIO), one of 25 commenters.

The American Society of Gene & Cell Therapy (ASGCT) noted that “new innovations in manufacturing have lagged behind other areas in the field” and that “the creation of a product agnostic pathway is an important step toward the field’s adoption of new technologies.”

But a common refrain in comments was that more information is needed on fundamental issues about how the program will operate.

The nonprofit API Innovation Center (APIIC) urged FDA to limit the program to AMTs developed and operated in the US, in line with domestic supply chain goals. Furthermore, APIIC asked whether FDA intends to target and encourage both generic and branded manufacturers.

San Diego-based biomanufacturing company Resilience asked for more information on the role of contract development and manufacturing organizations (CDMOs) and more detail in general.

“It is unclear how technology developers and CDMOs interact with the FDA in pursuit of an AMT designation outside of a product application,” Resilience wrote. “The draft guidance focuses instead on how the FDA will interact with [drug] applicants seeking to use a designated AMT in drug development or commercial manufacturing, leaving gaps in guidance on the AMT designation process itself.”

While the guidance aims to remove barriers to introducing new manufacturing technologies, the scope and benefits are unclear, according to BIO.

“In addition, this guidance needs further elaboration as to how this designation differs from existing programs and if they can be utilized separately or synergistically,” BIO wrote.

Resilience asked the agency what an “expedited” quality review means versus a standard quality review.

“The benefit of the program should be clear – to speed the of review of product applications through standardization and validation of the manufacturing technology well in advance of it being used for a product,” Resilience wrote.

PhRMA urges broad scope, wide swath of innovations

In its comments, the Pharmaceutical Research and Manufacturers Association (PhRMA) asked FDA to explicitly recognize a broad scope for the program, in line with congressional intent, to ensure a wide swath of manufacturing innovations, including “novel analytical methods, process analytical technology and real-time release testing that ‘substantially improve the manufacturing process.’”

The International Society for Pharmaceutical Engineering (ISPE) expressed concerns about data requirements, noting that innovative technologies rarely have enough data in early development to demonstrate a high level of improved manufacturing reliability for quality assurance.

“Therefore the benefits of AMT designation may not be fully realized by a sponsor with a potentially innovative technology for which data may be limited to substantially demonstrate improvements in manufacturing reliability or increased quality assurance,” the organization commented. “ISPE recommends that the guidance states that information including prior knowledge and/or data, where applicable, may be acceptable for determining AMT designation.”

Separate guidance for biologics?

Several stakeholders asked FDA to elaborate on treatment of and processes for biologic products in the AMT program.

UK-based gene and cell company Oxford Biomedica suggested the agency could provide examples of technologies that would be candidates for the AMT program. The company asked for more “additional, explicit” information on AMT designations for biological products and proposed separate guidance on this topic.

The National Institute for Innovation in Manufacturing Biopharmaceuticals (NIMBL) noted that it could be challenging to understand what an AMT is given the different technical standards across small molecules, generics, biologics, biosimilars, and emerging modalities. Separate AMT guidance for biologics could help, NIMBL suggested.

“This would allow FDA to offer more detail with respect to requirement and benefit and allow the Agency to build upon the concept of context so carefully advanced in the Guidance,” NIMBL wrote.

Several commenters said they would like FDA to change its position that biologics license applications (BLAs) should not incorporate by reference a designated AMT, including by referencing a drug master file (DMF) that contains a designated AMT, because the BLA holder should have knowledge of and control over the manufacturing process.

“Indeed, it is unclear how a BLA sponsor might reference a designated AMT outside the context of a DMF,” PhRMA explained. “Prohibiting use of a DMF for BLAs utilizing designated AMTs undermines the plain language of the statute and Congress’s intent in facilitating broad use of advanced manufacturing technologies and encouraging innovation in this space.”

The ASGCT flagged the same issue and also disagrees with FDA’s plans for interaction with CBER’s Advanced Technologies Team (CATT) before AMT designation.

“This limits the ability for technologies to qualify for AMT, both definitionally and logistically given the existing limitations and bottlenecks associated with CATT,” the ASGCT wrote.

“The Society requests greater clarity on the attributes of technologies that are appropriate for the CATT and AMT programs and the removal of the tie between the programs’ entry criteria,” ASGCT added. “If FDA does not remove these links, the final guidance should provide information regarding how CATT will help determine and advance the appropriate level of maturity for AMT designation.”

Industry clamors for clarity on FDA’s advanced manufacturing designation program

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