CMC and Quality Enhancements Under PDUFA VII Explained

FDA establishes numerous enhancements to product quality and chemistry, manufacturing, and controls (CMC) approaches in PDUFA VII to facilitate timely access to safe, effective, and innovative new medicines for patients, including:

• product quality reviews;
• CMC readiness for products submitted under accelerated pathways;
• advancing utilization of innovative manufacturing technologies;
• performance goals for review of original manufacturing supplements.

Enhancing Product Quality Reviews

The primary focus of PDUFA VII is improving communications during drug development and application review.

FDA will utilize the “Four-Part Harmony” approach for CMC information requests (IR) to promote an efficient and effective application review process and enhance communication between FDA and Sponsors at appropriate time points within the review cycle and product lifecycle.

The Four-Part Harmony approach includes the four essential components of CMC IRs, which will communicate the FDA’s position on the following:

• acknowledge what was provided and where;
• identify what the issue or deficiency is;
• identify what information is needed to achieve resolution and make a regulatory decision;
• justify why it is needed to achieve resolution and make a regulatory decision.

FDA has further committed to update and conduct training on the CDER Manual of Policies & Procedures (MAPPs) and the CBER Standard Operating Procedures and Policies (SOPPs) on product quality IRs by the end of the fiscal year 2023 to promote FDA reviewers’ use of Four-Part Harmony.

In addition, FDA will enhance communication related to pre-license and pre-approval inspections, which will help the sponsors with inspection readiness preparation.

Under PDUFA VII, FDA is targeting to communicate its intent to inspect a manufacturing facility for BLA pre-license inspections and NDA pre-approval inspections at least 60 days in advance and no later than the mid-review cycle. Although, per PDUFA VII, FDA maintains the right to inspect manufacturing facilities at any time during the review cycle.

Lastly, the COVID-19 public health emergency has triggered a need for FDA to expand the use of alternative tools to assess facilities named in the application.

Based on recently gained experience, FDA will develop and issue guidance documents and policies discussing the best practices for using alternative tools, including:

• requesting existing inspection reports from other trusted foreign regulatory partners
• requesting information from applicants
• requesting records and other information directly from facilities and other inspected entities
• utilizing new or existing technology platforms to assess manufacturing facilities

FDA is targeting September 30, 2023, to issue a draft guidance.

CMC Readiness for Products Submitted under Accelerated Pathways

As accelerated clinical development programs often face challenges in expediting and aligning CMC development activities, PDUFA VII outlines FDA goals to enhance CMC readiness for accelerated-track products.

FDA will develop a new MAPP on approaches to address challenges in expediting and aligning CMC development activities for CDER-regulated products with accelerated clinical development timelines.

The MAPP will describe FDA’s early engagement with Sponsors, including science- and risk-based approaches, modern pharmaceutical principles, and modern regulatory tools detailed in ICH Q12 Technical and Regulatory Considerations for Pharmaceutical Product Lifecycle Management.

Beginning in the fiscal year 2023, FDA will conduct a CMC Development and Readiness Pilot (CDRP) to accelerate the CMC development of products under an IND application. 

Sponsors participating in the CDRP will benefit from two additional CMC-focused Type B meetings and other CMC-focused discussions based on readiness and defined CMC milestones.

By December 31, 2022, the FDA will publish a Federal Register Notice (FRN) announcing the pilot and outlining the eligibility criteria and process for submitting a request to participate.

FDA also announced that starting April 1, 2023, they will accept requests to participate in the CDRP program and select no more than nine proposals, with approximately two-thirds being CBER-regulated products and one-third CDER-regulated products.

The FDA will issue a new Federal Register notice to announce pilot programs for the three following fiscal years.

For more details, visit Federal Register :: Chemistry, Manufacturing, and Controls Development and Readiness Pilot Program; Program Announcement.

FDA will also conduct a public workshop by July 31, 2025, to focus on CMC aspects of expedited development (i.e., case studies, lessons learned, and stakeholder input on the CMC Development and Readiness Pilot) and create a strategy document on how to proceed with developing or revising other policies and on proposed timeframes for the specific actions.

Advancing Utilization of Innovative Manufacturing Technologies

Another key PDUFA VII provision is the FDA’s commitment to conduct a public workshop by the fiscal year 2025 to focus on utilizing innovative manufacturing technologies for CDER- and CBER-regulated products. The workshop will include best practices, lessons learned, case studies, barriers to adoption, and regulatory strategies for advanced manufacturing technologies.

Following the close of the public comment period for the public workshop, FDA will draft a strategy document.

Performance Goals for Review of Original Manufacturing Supplements

The performance goals for reviewing original manufacturing supplements set in PDUFA VII remain the same as previously outlined in PDUFA VI.

FDA targets to review or act on 90% of prior approval supplements (PAS) within four months of the receipt date and 90% of all other manufacturing supplements within six months of receipt. 

If you have questions about CMC enhancements or any other PDUFA VII Updates, email info@mmsholdings.com to speak to a regulatory or CMC expert.

By: Margaret Studzinska, Associate Director, CMC and Nonclinical Writing and Nancy Hsu, Regulatory Affairs Associate

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