Combo products, drug industry groups seek more clarity about cross-center master file guidance

Groups representing drugmakers and combination product manufacturers have asked the US Food and Drug Administration (FDA) for more clarity on its recently published draft guidance on the use of cross-center master files (MF). More specifically, they asked how the agency will address master file deficiencies, communication between product centers and sponsors, center responsibilities, and more.

In November, FDA issued a draft guidance explaining where sponsors of combination and non-combination premarket applications should submit cross-center master files that are referenced and intended to support more than one regulatory submission. The master files are voluntary submissions that provide confidential information about the facilities, processes, or materials used for manufacturing, packaging, and storage of FDA-regulated products. They may also include other types of information, such as nonclinical evaluations, including toxicology data or Risk Evaluation and Mitigation Strategies (REMS). (RELATED: FDA guidance outlines where to send “cross-center” master files, Regulatory Focus 25 November 2025)

The Combination Products Coalition (CPC) told FDA that while the draft guidance clarified questions such as where to submit information for different product types based on the constituent type and intended submission, it missed opportunities to streamline the combination product development pathway using master files and made several suggestions.

CPC noted that FDA issued a draft guidance in 2024 on platform technology designation that excluded device constituents and referred sponsors to its 2019 draft guidance on bridging for drug-device and biologic-device combination products to leverage information previously submitted in an approved new drug application (NDA) or biologics license application (BLA). However, the group also noted that the guidance has not yet been finalized and isn't on the agency's most recent guidance agenda. It argued that the new master file guidance could be used instead to address device constituent information.

CPC elaborated that master files could provide similar device constituent information, such as design descriptions, performance testing, software information, and device manufacturing information from NDA and BLA sponsors. Ultimately, it advocated for allowing sponsors to use master files as a regulatory tool to leverage device constituent information and eliminate the need for redundant design, testing, and review.

“CPC recommends that the Draft Master File Guidance be updated to include ways sponsors and reviewers should leverage MFs and recognize previously reviewed MFs to eliminate redundant reviews of well-characterized device constituent platforms,” said CPC.

CPC raised concerns that implementing the recommendations in the draft guidance retroactively could delay product reviews, and the master file holder may change where they submitted their master files based on the final guidance.

“CPC is concerned that this may lead to potential delays if reviewers do not have access to the new hosting center MF systems,” said CPC. “CPC recommends that this policy is not implemented retroactively; rather, it should only apply to new MF submissions.

“Additionally, the Agency should prioritize updates to reviewer MF access for CDER, CBER, and CDRH master files to ensure seamless implementation of the Draft Master File Guidance policies,” the group added.

CPC noted that the guidance does not state what FDA plans to do when it identifies deficiencies in the master files during a product review. The group said that, based on recent experience, the agency may discuss the matter with the master file holder without also notifying the authorized party, or delay the notification. It said the lack of communication and expectations creates significant challenges for the sponsor in terms of regulatory planning and risk management.

“CPC recommends that the Draft Master File Guidance clarify that applicants are made aware of MF deficiencies that materially affect a marketing application under review,” said CPC.

CPC said FDA could notify the sponsor of the deficiency within a day of discovery and disclose the deadline for the master file holder's response, without revealing proprietary details. It said FDA could also encourage coordinated timelines and communication between the agency, the master file holder, and the sponsor when resolving the deficiency is critical to the product review.

“For non-combination products, the Draft Master File Guidance states that in instances where a MF could be referenced by more than one center, the center that will receive the first referencing submission is the recommended hosting center for the MF,” said CPC. “However, the Draft Master File Guidance does not state how to manage this circumstance for combination products.

“CPC requests that the same approach (i.e., the first referencing submission is the hosting center) is applied to combination products and that subsequent referencing by another later submission should not change the hosting location of the MF,” the group added. “CPC also requests further clarification within the Draft Master File Guidance on who to contact if there is a question on which center to submit the MF.”

CPC also asked that the Office of Combination Products (OCP) be used as the point of contact when clarity is needed.

The Bulk Pharmaceutical Task Force (BPTF) also wrote to FDA and asked it for several clarifications regarding when and how master files should be submitted across the product centers. The group noted that while the Center for Drug Evaluation and Research (CDER) and the Center for Veterinary Medicine (CVM) publish public drug master file (DMF) lists, the Center for Biologics Evaluation and Research (CBER) and the Center for Devices and Radiological Health (CDRH) do not currently publish equivalent product master file lists. It urged the agency to publish all product master file lists publicly to improve planning and coordination.

Furthermore, BPTF asked FDA to clarify its cross-center access and communication processes. More specifically, it asked how the agency will operationalize cross-center access, communication, consults, and amendment notifications. It also asked how it plans to address version control in cases with multiple reviews and handle disputes between product centers.

BPTF also urged FDA clarify its formal criteria or provide a decision tree to ensure its policies are consistent when assigning hosting product centers across master file types and product categories.

“It is unclear how existing MFs will be handled under the new hosting model — whether they will remain with their historical Center, be subject to optional migration, or be subject to enforced adjudication,” said BPTF. “What will happen to older MFs hosted in less aligned Centers?

“Additional guidance is needed on whether [letters of authorization (LOA)] require specific elements or formatting when an MF will be accessed by multiple Centers, and how LOAs will be processed or validated across Centers to ensure consistent access,” the groups added. “Consider the current Drug DMF LOA template.”

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Combo products, drug industry groups seek more clarity about cross-center master file guidance

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