The Latest Current FDA CBER Initiatives

[Editor’s Note: This article was first distributed by Lyophilization Technology, Inc. and is reprinted with permission.]

Also referenced was the recent CARsgen Warning Letter issued in July 2024. Highlights of the warning letter were inadequate environmental monitoring, cleaning procedures and visual inspection practices. Daniel emphasized the importance on maintain GMP controls that are appropriate to the product development lifecycle, referencing the “Current Good Manufacturing Practice for Phase I Investigational Drugs” guidance document.

Daniel summarized some of the 48 Warning Letters year-to-date, with the most frequent citations related to:

• Environmental Monitoring (16)
• Laboratory Controls and Stability (10)
• Process Validation (6)

Issues with the Quality Unit oversight were mentioned but were relatively less in number (3), matching the number of citations for Facilities and Equipment Maintenance.

Specific Code of Federal Regulations (CFR) references cited included:

• Environmental Monitoring
• Control of Microbial Contamination (211.113(b))
• Design and Construction Features – Aseptic Processing (211.42(c)(10))
• Laboratory Controls and Stability Testing
• General Requirements (211.160)
• Stability Testing (211.156)
• Special Testing Requirements (211.167)
• Process Validation
• Written Procedures: Deviations (211.100)

The top of the list of concerns was inadequate microbial contamination control, including failure to validate aseptic processes and to conduct media fills effectively.

Additionally, two sectors of the industry that discussed having notable GMP concerns were ophthalmic and cell and tissue products, specifically about firms distributing unapproved products. In one case, a regenerative ophthalmic medicine was marketed but was never approved by the U.S. FDA. This product investigation, due to its nature, was a collaboration between the Office of Investigative Integrity, the Center for Drug Evaluation and Research and the CBER branches.

Recent inspection findings pointed to poor environmental monitoring procedures, inadequate cleaning methods, and failures to investigate excess bulk solution bioburden marked as "too numerous to count". Questions were also raised regarding filtration sterilization validation under challenging bioburden conditions.

Equipment maintenance deficiencies were also noted, including the discovery of “black growth” on HEPA filters and facility issues such as gaps in ceilings, cracked surfaces, peeling paint and “pooling water collection”.

Beyond microbial contamination, particulate control and detection methods were discussed as areas of heightened concern. Particular challenges arose with novel therapies that are inherently opaque, which complicates visual inspection. Inadequate visual inspection criteria and ineffective Corrective and Preventive Actions were noted to be contributing to contamination risks and questions of product quality. Additionally, Daniel mentioned the lack of assessment of the level of particulates that may exist in product-holding bags. This brings into question the control of the supply chain, such as having adequate vendor audits and Quality Agreements.

An increase in container/closure integrity issues for prefilled syringes was also noted. These issues have led to vaccine recalls, with syringe flange failures posing injury risks to those administering the product. Luer Lock adapters were reported to have a potential for leaking with a surprising number of Biological Product Deviation Reports submitted. Daniel emphasized the need for better vendor management within the supply chain to address these concerns.

Daniel identified three key points regarding biological drug products, with a particular focus on regenerative medicine:

1. Biological drug products must either have an approved Biologics License Application or be in clinical trials with an active Investigational New Drug Application.
2. FDA Compliance Letters serve as a prompt to align firms with regulatory expectations.
3. Daniel encouraged companies developing novel regenerative medicine products to engage with the agency early during development.

Deniel’s presentation prompted several questions from the audience. These included compliance expectations and interpretations and requirements of GMPs. One question was regarding the need to do three, and specifically three aseptic process simulations for validation of aseptic processing. Daniel’s answer provided wise guidance in response, which is to conduct enough validation studies to provide confidence that the process is within adequate control.

The PDA Delaware Valley meeting was a great opportunity to gain awareness of what the agency is seeing as areas of interest based on recent observations. The presentation was a good reminder of basic requirements, such as contamination control in the preparation of sterile products. It was also a good avenue for the agency to pass along areas of concern and interest and a reminder of critical aspects to consider.