PreCheck Pilot Program Structure

Introduction

This content provides more detailed information for the FDA PreCheck Pilot Program.

The FDA PreCheck Pilot Program seeks to accelerate the establishment of new pharmaceutical manufacturing facilities in the U.S. to strengthen the domestic drug supply chain through a two-phase approach that provides early engagement, structured feedback, and expedite assessments of facility information in a drug application. As part of the Pilot Program, FDA expects to provide accepted participants with a dedicated point of contact who will facilitate communication throughout the process. The pilot program is intended to include a kickoff meeting to provide an overview of program expectations, followed by regular check-ins at agreed-upon milestones. Participants may also receive a post-site visit meeting to discuss findings. Additionally, the pilot program offers an opportunity for pre-submission meeting(s) specific to facility evaluation in the context of a product-specific application, as well as additional meetings upon request when further discussion is needed.

The PreCheck Pilot Program is designed to be flexible and may be tailored to meet the unique needs of individual participants. This approach may be updated as we gain additional insights to better support the short-term and long-term program goals.

Phase 1: Facility Readiness

Early engagement and support for new pharmaceutical manufacturing facilities through Pre-Operational Reviews (POR) that assess facility design and construction, equipment design and qualification, and Pharmaceutical Quality System (PQS) design to achieve facility readiness and facilitate development of the Type V Drug Master File (DMF) used to support Phase 2.

Phase 2: Application Submission

Structured pre-submission engagements with the aim to support expedited facility evaluation and enable earlier inspection timelines in the review cycle. The figure below provides a high-level overview of Phase 1 and Phase 2 of the PreCheck Pilot Program. Additional details about the specific phases of the program can be found below in subsequent sections.

PreCheck Pilot Program Overview of Phase 1 and Phase 2

Phase 1: Facility Readiness

Overview and Objectives

Phase 1 provides early engagement and support for new pharmaceutical manufacturing facilities through two integrated components: the POR and the Type V DMF.

Manufacturers receive structured FDA feedback from initial facility design through pre-production activities during the POR, while simultaneously building a comprehensive facility information repository in the Type V DMF. These two components work in tandem: as POR engagements occur, facility information is documented and updated in the Type V DMF, creating an integrated, dynamic record that may support future drug applications.

Pre-Operational Review (POR)

The POR provides a structured framework for early engagement between FDA and manufacturers during the facility development process. Through formal engagements, FDA provides timely feedback on facility and Pharmaceutical Quality System (PQS) design concepts. This early engagement ensures principles of good design are implemented prior to construction and equipment installation, enabling necessary changes to be made early to mitigate downstream risks associated with delays or non-conformance to CGMP requirements. Later in the POR, FDA verifies the facility was constructed according to reviewed plans and assesses whether it has been equipped as outlined in the final design plans and documentation in the Type V DMF.

The POR may include a site visit. The site visit is not an inspection but note that all expectations outlined in the applicable Compliance Program and the Investigations Operations Manual (IOM) will be used to give FDA’s best assessment at the time as to whether the facility is ready for pre-submission meeting(s).

PreCheck Pilot Program - Pre-Operational Review (POR) Process

The above figure outlines at a high-level the anticipated POR process that will encompass the following POR Elements:

Element 1 - Design Review: Review of facility and PQS design concepts
Element 2 - Pre-Construction Review: Review of final design prior to construction, following completion of any necessary modifications
Element 3 - Equipment Installation and Qualification Review: Review of equipment design and installation plans
Element 4 - Pre-Production Review: Assessment of facility construction, equipment installation, and readiness for production activities

POR Engagement Methods

Engagements throughout the POR may occur through teleconferences, email correspondence, or other appropriate communication methods, based on the facility's development timeline and the complexity of the issues under review. The POR may also include remote site assessment(s) and site visit(s) as appropriate, with meeting minutes and site visit memorandum utilized to document POR activities.

Type V Drug Master File

What is a Type V DMF?

DMFs are submissions to FDA that provide confidential, detailed information about facilities, processes, or articles used in the manufacture of drug products. FDA currently utilizes several types of DMFs, ranging from Type II-V (Type I DMFs are no longer used).

A Type V DMF is an existing regulatory tool that can be leveraged for "FDA-accepted reference information" (see 21 CFR 314.420(a)(5)). In the context of PreCheck, the Type V DMF serves as a central repository for all facility-related information reviewed during the POR that can be referenced in future applications. FDA intends to provide further information on the content and procedures for preparing and submitting a Type V DMF to support the PreCheck Pilot Program. **Note: FDA typically reviews DMFs upon reference in the context of a regulatory submission. By contrast, FDA intends to actively assess Type V DMFs submitted under the PreCheck Pilot Program and provide relevant and timely feedback FDA intends to provide participants with additional information on ongoing Type V DMF maintenance and updates to ensure facility information remains current.

Integration of POR and Type V DMF:

Throughout Phase 1, the POR and Type V DMF function as complementary tools. As the physical build of the facility occurs and POR engagements take place, the Type V DMF is built in parallel as the central repository of facility information. Information in the Type V DMF supports assessments and discussions during POR engagements. As well, facility information that is updated and refined as a result of discussions during POR is documented and updated in the Type V DMF, creating a comprehensive file that will support Phase 2 activities and future drug applications. This integrated approach ensures that knowledge gained during early facility development is captured systematically and can be leveraged efficiently throughout the facility's operational lifecycle. The below figure outlines anticipated Type V DMF details as a PreCheck Support Tool.

PreCheck Pilot Program - Type V DMF details as a PreCheck Support Tool

Benefits of Using a Type V DMF:

Utilizing a Type V DMF for facility-related information provides numerous benefits:

Facilitates structured FDA engagement with industry: A Type V DMF provides a central repository for facility information as it develops.
"Qualify Once, Reference Many": A single Type V DMF can be referenced in multiple applications, potentially eliminating the need to resubmit product agnostic facility information for each product. This is a potential benefit for manufacturers planning to produce multiple products at the same facility.
Expedited FDA Assessment: Reduces FDA's burden to review the same facility and equipment qualification information repeatedly across multiple applications.

Amending DMF Technical Information:

DMF holders are responsible for ensuring their DMF remains current and that they adhere to the commitments and representations contained within it. Technical information in the DMF may need to be updated over time, both during participation in PreCheck and during routine maintenance of the DMF after completion of PreCheck to support regulatory submissions.

Phase 2: Application Submission

Overview and Objectives

Upon completion of Phase 1 activities, including development of the Type V DMF with sufficient coverage and depth and conclusion of POR engagements, participants transition to Phase 2. The comprehensive facility information and FDA knowledge gained during Phase 1 serve as the foundation for expedited application review and inspection processes in Phase 2.

Phase 2 begins with pre-submission meetings and other established interactions per existing user fee programs between the facility/applicant and the FDA prior to submission of the first drug application (NDA, ANDA, BLA) that will use the new facility. These engagements help address potential manufacturing facility issues related to the application before submission. Building on Phase 1 knowledge, Phase 2 aims to incorporate facility information into specific application assessments through two integrated components.

CMC Facility Pre-Submission Meetings

The following element of the Application Submission Phase is intended to help facilitate enhanced and accelerated quality assessment:

Pre-application Meetings and Engagements:

Provide applicants and their manufacturers the opportunity to give FDA advanced awareness of facility and facility-related manufacturing strategies for specific drugs in forthcoming applications, while enabling earlier assessment and inspection activities within the review cycle.
Enable FDA to provide facility-related Chemistry, Manufacturing and Controls (CMC) feedback on anticipated data or logistical needs to support timely review and inspection processes.
Allow FDA to “frontload” significant elements of facility assessments for applications from new U.S. facilities through early facility engagement and assessment activities.

Expedited Application Review and Inspection Processes

Building on Phase 1 knowledge, FDA can support timely review of facility components of the application and inspection processes. As FDA reviews specific product applications, the Phase 1 information and pre-application meeting(s) provide advanced awareness of the facility and facility-related manufacturing strategy for the specific drug in the forthcoming application. This knowledge enables FDA to make earlier and more informed inspection determinations. Leveraging information about the facility from Phase 1 provides these opportunities for efficient use of industry and FDA resources during application assessment in Phase 2.

Important Limitations and Considerations:

For new U.S. manufacturers of active pharmaceutical ingredients (APIs), FDA might also review and provide feedback on their Type II DMF prior to the assessment of a drug product application (NDAs or ANDAs only) that references the Type II DMF. Typically, DMFs are reviewed only when the referencing application is assessed, so this would represent an earlier review opportunity. Such strategies and requests should be discussed early in Phase 2, ideally as part of a pre-submission meeting.

The overall application review timeline is ultimately governed by several factors depending on the application type (e.g., user fee program, clinical, bioequivalence, and other non-facility-related CMC elements may control the review clock).

Benefits for Subsequent Applications:
After the first application is approved, subsequent applications submitted by participants of the PreCheck Pilot Program using the same facility may benefit from the established knowledge base, potentially enabling accelerated inspection determinations within the review cycle or leveraging existing information to confirm the facility meets standards for approval.

Additional Resources: