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The Parenteral Drug Association Delaware Valley Chapter hosted Daniel DeCiero of OCBQ, CBER to present the latest quality and compliance considerations. Daniel provided participants an overview of compliance aspects and gradually shifted focus toward specific product-related topics of recent concern to the agency. His presentation included points on biological products, ophthalmics, cell and tissue products, and prefilled syringes.
Regulatory insights drawn from product approval dossiers and inspection assessments offered thought provoking perspectives. These included observations noted on FDA 483 forms, various Warning and Untitled Letters, and “It has come to our attention…” letters.
Daniel also addressed notable quality issues of concern identified by the agency, particularly emphasizing the control of microbial contamination, particulate control, and prefilled syringe container/closure integrity. Points were also made regarding investigational cell and gene therapy products.
Also referenced was the recent CARsgen Warning Letter issued July 2024. Highlights of the warning letter were inadequate environmental monitoring, cleaning procedures, and visual inspection practices. Daniel emphasized the importance to 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 observations related to:
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Environmental Monitoring (16)
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Laboratory Controls and Stability (10)
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Process Validation (6)
Issues with the Quality Unit oversight were mentioned but were relatively less in number (3), matching those 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 (211.113(b))
The top of the list for 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 FDA. This product investigation, due to its nature, was a collaboration between OII, CDER and CBER branches.
Recent inspection findings pointed to poor environmental monitoring procedures, inadequate cleaning methods, and failures to investigate excess bulk solution bioburden marked as TNTC. 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 CAPAs were noted to be contributing to contamination risks and questions of product quality. Additionally, Daniel mentioned the lack of assessing 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 BPDRs submitted. Daniel emphasized the need for better vendor management within in the supply chain to address these concerns.
Daniel identified three key points regarding biological drug products, with a particular focus on regenerative medicine:
- Biological drug products must either have an approved BLA or be in clinical trials with an active IND.
- FDA Compliance Letters serve as a prompt to align firms with regulatory expectations.
- Daniel encouraged companies developing novel regenerative medicine product toengage 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 APS’s for validation of aseptic processing. Daniel’s answer provided wise guidance in response; 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 upon recent observations. The presentation was a good reminder of basic requirements, such as in 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.
About PDA Delaware Valley: A branch of the non-profit Parenteral Drug Association (PDA), the Delaware Valley Chapter serves as a forum through which technical professionals in Pennsylvania, Delaware, and Southern New Jersey advance the science of development, manufacturing and marketing of parenteral pharmaceuticals, biopharmaceuticals, and chemicals.
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