Key Insights from FDA’s Draft Guidance on FAQs for CGT: Quality and Regulatory Interactions

Published on: February 5th, 2025

The FDA has recently released a draft guidance titled “Frequently Asked Questions — Developing Potential Cellular and Gene Therapy Products,” aimed at assisting developers in the regulatory landscape of cellular and gene therapy (CGT) products. The document provides guidance on product development, regulatory collaboration, non-clinical and clinical development. This blog post focuses on quality recommendations and Agency interactions. 

Product Development Considerations

The guidance emphasizes several key aspects: 

• Donor Eligibility: this is a paramount component in CGT derived from human cells or tissues. FDA provides distinct guidance for autologous and allogeneic donors. For both donor types, robust traceability systems are crucial to track donor material from collection to final product.  

FDA kicked off 2025 by issuing five guidance documents providing recommendations on determining eligibility of donors and reducing the risk of transmission of infectious diseases. More details can be found in FDA website. 

• Autologous donors: the focus is on verifying the donor’s identity to ensure the correct cells are used throughout the manufacturing process. While eligibility screening for diseases is generally not required, sponsors must ensure proper documentation and traceability. 

• Allogeneic donors: these require rigorous screening and testing to confirm eligibility. This includes evaluations for communicable diseases, as well as donor health assessments to reduce risks associated with cell or tissue variability. Sponsors are expected to document these procedures and ensure compliance with 21 CFR 1271.  

• Critical Quality Attributes (CQAs): identifying CQAs early in the development process is crucial for building reliable manufacturing processes, as CQAs are necessary for assessing analytical comparability when introducing process changes. Potency is a challenging CQA that needs to be addressed from early stages. 

• Analytical Methods: description of non-compendial methods as well as demonstration of suitability is needed for First-In-Human (FIH) studies. At FIH safety methods should be validated and dose-determining assays should be qualified. Description of the qualification protocol and data to back up the accuracy, precision, sensitivity and specificity should be included in the IND. For compendial methods that are different from USP, details on how methods are executed and whether their performance aligns with the characteristics of the corresponding USP methods should be provided. 

• Process Characterization and Validation: characterization can be executed by using scale-down models representing the commercial manufacturing process, while process validation should occur at commercial scale with multiple process performance qualification (PPQ) lots to demonstrate consistency. How many PPQ lots are necessary?  Although three is the minimum in common practice, no fixed number of PPQ lots is required; it should rather be determined by a risk assessment and should be sufficient to demonstrate consistent consecutive manufacturing. 

• Manufacturing Changes: sponsors should evaluate comparability to demonstrate no adverse impact on the product’s quality or safety. FDA encourages manufacturers to discuss with FDA the manufacturing changes and comparability protocols prior to conducting the studies. 

• Stability: stability data is essential at all development stages. For early-phase trials, stability data can be derived from non-clinical, engineering, or similar product lots stored under conditions matching the clinical material, allowing for an incremental approach for setting acceptance criteria. 

• BLA preparation: CMC development evolves with clinical development. For BLA submission, the manufacturing process and all analytical methods performed to support product quality must be validated. The data provided should support product safety, purity, potency, and stability. 

Interacting with FDA

Effective communication with the FDA is vital throughout the development process. Key interaction points include: 

• Early Engagement: INTERACT and pre-IND meetings can address early-stage questions, potentially saving time in later stages. 

• Expedited Pathways: rolling reviews are available if a Drug Product has Fast Track, Breakthrough Therapy, or Regenerative Medicine Advanced Therapy (RMAT) designation and if certain criteria are met. Rolling review should be requested as part of the information package for the pre-BLA meeting. If FDA agrees, a maximum of 12 months should elapse from the first submission of BLA content to the final submission to complete the BLA. 

Why it matters

This guidance reinforces the FDA’s commitment to advancing regulatory science while supporting innovation in transformative therapies. For developers, the message is clear: prioritize quality early and stay connected with the FDA to bring safe and effective treatments to patients faster. 

The FDA is accepting comments on this draft guidance until February 18, 2025.