FDA’s OTP Town Hall Clarifies CMC and Facility Readiness Standards for Gene Therapy BLAs

The FDA’s Office of Therapeutic Products (OTP) within the Center for Biologics Evaluation and Research (CBER) hosted its Virtual Town Hall to address chemistry, manufacturing, and controls (CMC) expectations and facility readiness for Biologics License Application (BLA) submissions and post-licensure changes in gene therapy manufacturing.

Moderated by Kimberly Schultz, Director of the Division of Gene Therapy, the event brought together regulatory leaders Jacob Bitterman, Jessica Chery, Christine Harman, and Loni Warren Henderson from the Office of Gene Therapy and the Office of Compliance and Biologics Quality (OCBQ). The session marked the first time OTP and OCBQ jointly addressed facility readiness, reflecting growing alignment between product reviewers and inspection teams as gene therapy manufacturing enters the commercial mainstream.

Risk-Based Inspections and Pre-Licensure Readiness

The panel opened by clarifying the FDA’s risk-based inspection model, explaining that not all facilities listed in a BLA are automatically inspected. Priority is given to facilities performing critical manufacturing activities—including drug substance, drug product, and aseptic operations—or those using novel technologies and first-in-class biologic processes.

Inspection history is also a determining factor. Facilities with strong compliance records and a consistent inspection history may qualify for inspection waivers, while new facilities, particularly those overseas, should anticipate full pre-approval inspections. Harmon emphasized that inspection expectations are identical for U.S. and foreign facilities, though the latter may face logistical challenges such as travel coordination or collaboration with foreign regulatory authorities.

Manufacturers submitting their first BLA were reminded that inspection readiness should be achieved at the time of submission, not later in the review cycle. Inspections are typically targeted for mid-cycle to allow sufficient time for FDA review and follow-up before the regulatory decision date. Failure to achieve inspection readiness can delay or negatively impact BLA approval timelines.

Defining Post-Approval Changes and Risk Management Frameworks

Bitterman explained the FDA’s structured approach to categorizing post-approval manufacturing changes under the Chemistry, Manufacturing, and Control Changes to an Approved Application: Certain Biological Products (June 2021) guidance.

Changes are classified into three reporting categories based on risk:

• Prior Approval Supplement (PAS): Required for high-risk changes that may affect identity, strength, purity, or potency—such as scaling up production or adding a new manufacturing site.
• Changes Being Effected (CBE-30 or CBE-0): Appropriate for moderate-risk changes, allowing product distribution after 30 days (CBE-30) or immediately (CBE-0) if no FDA objection.
• Annual Report: Used for low-risk modifications with minimal potential impact on product quality.

For scale-up operations, a PAS is typically required, while automation of manual steps may be reported as CBE-30 if product quality risk is low. Bitterman advised manufacturers who are uncertain about classification to engage their FDA Regulatory Project Manager (RPM) early to avoid reclassification delays during review.

Expanding Manufacturing Capacity: Key Requirements

Chery outlined that adding a new GMP facility to increase manufacturing capacity represents a major regulatory change and therefore requires FDA approval via a Prior Approval Supplement.

The PAS must include a comprehensive risk assessment following ICH Q9, documentation of technology transfer, and justification for the expansion. It should also include comparability studies demonstrating product equivalence across facilities in terms of identity, purity, potency, strength, and stability.

Chery encouraged manufacturers to submit a comparability or post-approval change management protocol (PACMP) for FDA feedback before executing studies. The validation section should include process performance qualification (PPQ) data, analytical method comparability, and full-scale lot comparability.

Harman added that the PAS must also contain detailed facility design and environmental control data, including diagrams showing personnel and material flows, HVAC qualification summaries, and cross-contamination control strategies.

FDA expects all facility qualifications to be completed and the site to be inspection-ready at the time of submission. Ideally, the facility should be in production so inspectors can observe live operations. When production frequency is low, the agency may accept mock runs, provided they are pre-coordinated with the review team.

Common Findings and Quality Oversight Deficiencies

Harman highlighted that the most frequent deficiencies observed during inspections of cell and gene therapy facilities relate to sterility assurance and quality system performance.

Deficiencies often include:

• Unvalidated aseptic processes and unclear aseptic boundaries.
• Lack of validation for sterile filters used in custom media or small-batch buffer preparation.
• Improper sterilization procedures for components introduced into the aseptic process.

FDA has observed repeated failures in CAPA (Corrective and Preventive Action) systems, including delays in closing deviations, incomplete root-cause analysis, and lack of effectiveness verification. These systemic gaps signal insufficient quality oversight, posing significant risks to product sterility and consistency.

Harman strongly advised manufacturers to validate all sterilization methods, including small-volume sterile filters, and ensure that every component entering the aseptic boundary is adequately controlled and documented.

Comparability Protocols: Accelerating Post-Approval Flexibility

Bitterman clarified that comparability protocols, also known as post-approval change management protocols (PACMPs), provide a structured framework for evaluating the impact of manufacturing changes.

These protocols describe the proposed change, associated risk assessment, testing strategy, and predefined acceptance criteria. When implemented correctly, they can streamline future FDA reviews and, in some cases, reduce the reporting category (for example, allowing a CBE submission instead of a PAS).

However, he noted that site additions always require a PAS, even with an approved comparability protocol, due to inspection requirements.

Analytical Methods, QC Laboratories, and Lifecycle Management

Chery and Bitterman explained that QC laboratories performing critical product release testing are subject to FDA inspection even if not fully described in the BLA. Analytical methods must be validated or bridged using risk-based lifecycle management per ICH Q14.

When analytical testing is transferred to a new site, equivalence must be demonstrated through validation and bridging studies comparing test results at both sites.

Regarding safety testing, Chery confirmed that replication-competent lentivirus (RCL) assays can be removed from the commercial release panel only after sufficient manufacturing and clinical data confirm consistent RCL-negativity, supported by patient monitoring data and submitted via a PAS.

Control of Raw Materials and Excipients

The FDA requires testing and qualification of all incoming materials—even proprietary or non-GMP-grade raw materials—under 21 CFR 211.84 and 610.15. Manufacturers must verify identity, purity, strength, and safety, often through supplier quality agreements and risk-based qualification plans.

For novel excipients, the level of data required is equivalent to that for a drug substance. Cross-referencing a Drug Master File is not permitted in BLAs. If the excipient is aseptically filled and administered separately, its manufacturing site may also require inspection; if incorporated directly into the product, it is evaluated under the sponsor’s overall quality system.

Stability Studies and Regulatory Flexibility

To justify product shelf life, FDA expects real-time stability data from at least three lots produced using the commercial process, though not necessarily the first three PPQ batches. Additional data can be submitted during the review cycle.

The draft ICH Q1 guidance introduces flexibility for gene therapy products (classified as ATMPs), allowing applicants to leverage clinical batch data or prior knowledge when commercial stability data are limited.

For lentiviral vectors used in CAR-T manufacturing, stability data must confirm maintenance of potency, identity, and sterility under proposed storage conditions, supported by qualified analytical methods.

Inspection Readiness Beyond Production

Harman and Warren Henderson noted that FDA recognizes several acceptable demonstrations of inspection readiness beyond live production, including mock manufacturing runs, system simulations, and personnel training exercises, provided they are discussed with the agency beforehand.

The panel also addressed common procedural questions—such as the inclusion of SOP-level detail in BLAs (not required if adequately summarized), cross-referencing between submission modules (hyperlinks strongly preferred), and device compatibility testing (expected in Module 3.2.P.2.6).

Key Takeaways: Regulatory Rigor Meets Practical Flexibility

The Town Hall underscored the FDA’s intent to balance regulatory rigor with scientific pragmatism as gene therapy transitions into large-scale manufacturing.

Manufacturers were urged to:

• Ensure inspection readiness by the time of BLA submission.
• Conduct comprehensive risk assessments for all facility and process changes.
• Use comparability protocols and pre-BLA meetings to align expectations early.
• Maintain robust CAPA systems and document all quality actions.
• Design stability and analytical programs that reflect real-world manufacturing conditions.

By clarifying these expectations, the FDA’s Office of Therapeutic Products aims to create a more predictable regulatory pathway for gene therapy developers—one grounded in scientific transparency, operational readiness, and continuous quality improvement.