Onshoring Drug Manufacturing: Insights from FDA’s PreCheck Initiative and Public Meeting

On September 30, 2025, FDA held a public meeting titled “Onshoring Manufacturing of Drugs & Biological Products.”  Driven by Executive Order 14293, “Regulatory Relief To Promote Domestic Production of Critical Medicines,” the meeting focused on reducing U.S. dependence on foreign pharmaceutical sources and promoting investment in domestic manufacturing.

FDA highlighted its new PreCheck Initiative as the primary mechanism to achieve this goal – streamlining and accelerating the establishment of high-priority U.S. facilities through early engagement between FDA and industry to address facility design, quality, and compliance issues before operations begin.  By increasing regulatory predictability and reducing delays, PreCheck aims to spur U.S. investment.  As multiple speakers emphasized, the greatest challenge is not science, but procedural and predictable regulatory execution.

The PreCheck Initiative: FDA’s Three-P Strategy

FDA, through the Center for Drug Evaluation and Research (CDER) and the Center for Biologics Evaluation and Research (CBER), introduced PreCheck as the core mechanism to streamline regulatory pathways for domestic manufacturing.  The initiative is built on two phases and three guiding principles – Partnership, Predictability, and Preparedness – intended to provide earlier and clearer guidance to reduce uncertainty for U.S. investment.

1. Phase 1 – Facility Readiness (De-Risking): This phase involves pre-operational reviews during facility design and construction. A key tool is the Type V Drug Master File (DMF), a facility-specific dossier capturing site layout, Pharmaceutical Quality System (PQS) elements, and maturity practices that can be referenced across multiple product applications.
2. Phase 2 – Application Submission: Leveraging Phase 1 knowledge, this stage focuses on aligning Chemistry, Manufacturing, and Controls (CMC) expectations, streamlining quality assessments, and enable earlier, more targeted inspections.

Dr. George Tidmarsh (CDER) emphasized that the COVID-19 pandemic exposed serious supply-chain vulnerabilities: over 50% of U.S. drugs are manufactured abroad, and most of the 168 essential medicines rely solely on foreign manufactured Active Pharmaceutical Ingredients (APIs).

Industry’s Two Core Barriers: Logistical and Post-Approval Hurdles

While industry participants broadly supported PreCheck, they were candid about the most significant regulatory hurdles to establishing new U.S. API facilities.  Representatives from innovator, generic, biologic, and contract manufacturing organizations (CMOs) identified several key challenges that must be resolved to unlock domestic capacity:

• Inspection Predictability & Decoupling

Industry expressed frustration over the timing and variability of Pre-Approval Inspections (PAIs), which are often conducted just weeks before a PDUFA date, creating significant risk of Complete Response Letters (CRLs).  Smaller API developers asked who should initiate PreCheck (sponsor vs CDMO), when engagement should occur, and whether FDA can provide checklists or process diagrams to assist smaller regulatory teams.  Others recommended stage-gated engagement plans aligned with construction, commissioning, and validation milestones – shared across FDA review teams to prevent conflicting feedback.

Stakeholders also urged FDA to decouple facility inspections from product application reviews, adopting a more risk-based, earlier inspection model triggered by events like media fills and engineering runs, rather than waiting until post-submission.  This issue is particularly challenging for complex biologics, where short-run manufacturing campaigns make the “inspection-while-in-production” model impractical.

• Post-Approval Flexibility (Especially for Biologics)

For well-characterized modalities such as monoclonal antibodies, FDA’s “one-size-fits-all” approach often requires a Prior Approval Supplement (PAS) even where a Changes Being Effected in 30 Days (CBE-30) or annual report would be scientifically justified.  This rigidity delays routine changes, such as site transfers or scale-ups — that are critical to expanding domestic capacity.

Stakeholders called for a risk-based CMC framework that leverages prior knowledge and platform technologies to shorten the critical path.  Because onshoring often involves expanding existing sites or replicating established production lines, industry urged FDA to reduce redundant data requirements (for example, stability or comparability studies) when prior knowledge supports predictability.

Participants also encouraged FDA to more fully operationalize the tools under ICH Q12: Implementation Considerations for FDA-Regulated Products.  Doing so could allow many post-approval changes to be downgraded from PAS to CBE-30 or annual reports when scientifically appropriate.  Several speakers proposed an “innovation track” for emerging technologies such as continuous flow chemistry and single-use systems, which would accelerate the adoption of advanced manufacturing approaches.

Key PreCheck Elements Supported by Industry

• Making the Type V DMF Work in Practice

A central component of FDA’s PreCheck proposal that could significantly accelerate domestic manufacturing is the establishment of a Type V facility Drug Master File (DMF) as the backbone of regulatory review.  A Type V DMF — a mechanism for submitting information to FDA that does not fit within the traditional DMF categories — can serve as a facility-centric repository of detailed information on manufacturing capabilities, quality systems, and compliance history.  By allowing FDA to review and reference this information across multiple product applications, a facility DMF would enable earlier and more targeted PAIs and reduce redundant reviews of the same facility data for each submission.

However, participants emphasized the need for FDA to issue a clear operating framework for the DMF’s use, ownership, and maintenance.  They suggested that FDA:

• Define the boundaries between reusable DMF content and product-specific application content (Module 3).
• Clarify how a single facility review, and inspection outcome can be leveraged across multiple sponsors.
• Provide guidance on updating and maintaining the DMF throughout a facility’s lifecycle so that it remains a living document rather than an administrative burden.

Stakeholders further advised FDA to pair the DMF approach with targeted meetings and transparent expectations for updates, reuse, and confidentiality, particularly for CMO/CDMO-owned facilities.

• Early, Continuous — and Informal — Communication

Another recurring theme was the importance of early, continuous, and informal communication throughout the facility development process.  Industry participants stressed that real-time engagement — from initial design through Installation Qualification (IQ), Operational Qualification (OQ), and Performance Qualification (PQ) — is far more valuable than relying solely on formal meetings and information requests.

Companies requested a single FDA point of contact, consistent reviewer assignments approximately 30 days pre-filing, and a collaborative forum for technical discussions on topics such as airflow, microbial control, and aseptic operations.  They also called for a smarter inspection strategy that leverages the facility DMF to decouple PAIs from product review timelines and introduces early inspection triggers (e.g., media fills or engineering runs).

• Integration with Other FDA Programs

Stakeholders encouraged FDA to integrate PreCheck with existing regulatory programs, including CMC modernization efforts, advanced technology designations, and PDUFA review processes.  Industry also asked FDA to clarify how Phase 1 PreCheck engagement applies to non-CMO sponsors and whether the Type V DMF remains the preferred vehicle in all cases.

The API Focus: Predictability and Platform Recognition

The afternoon session, which centered on API manufacturing, confirmed that this sector faces similar, but often more acute challenges.  Participants highlighted three recurring priorities:

1. Predictability and Early Engagement: The lack of transparent timelines and early communication remains the greatest barrier to establishing new U.S. API facilities.
2. Modernized, Risk-Based Oversight: Sponsors reiterated the need to decouple facility assurance from product reviews, using earlier and risk-based inspection triggers to avoid production delays.
3. Platform Recognition and Data Reuse: Industry again called for clear rules governing data reuse between the facility DMF and Module 3, as well as an innovation track for advanced manufacturing platforms such as continuous flow chemistry.

Sponsor/CDMO Action Items: Mobilizing Now

Industry participants signaled strong readiness to engage early to share design, PQS, and validation data early, if FDA provides clear service levels, confidentiality protections, and a “Record of Decision” mechanism to make early feedback binding and portable across the facility lifecycle.

To prepare for participation in PreCheck, companies should consider the following steps:

1. Drafting a Facility DMF Architecture: Clearly separate stable facility/PQS content (for the Type V DMF) from product-specific, variable content (for individual applications).
2. Proposing an Engagement Plan: Map out timing for engineering run and media fills, and propose earlier or alternative inspection options (e.g., remote assessments).
3. Documenting Prior Knowledge: Compile evidence of “copy-paste” line similarity and established control strategies to support reduced data packages for stability or PPQ studies.
4. Nominating a Single-Point-of-Contact: Establish a continuous communication cadence and request FDA to mirror it with a dedicated liaison team.

Overall, the tone of the meeting was optimistic.  If FDA can rapidly implement a PreCheck program that formalizes early, durable engagement, modernizes post-approval change pathways, and alleviates late-cycle inspection bottleneck, the pharmaceutical industry appears poised to translate expertise into faster, more resilience domestic manufacturing capacity.