Biologics

CBER Inspections Challenged by Lack of Facility Readiness

David McFarland

— 3 min read
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CBER says that a common deficiency that is driving a significant share of BLA-related complete response letters (CRLs) is manufacturing facility readiness, and companies are routinely misjudging when their facilities are actually prepared for an FDA inspection. In remarks delivered to the Food and Drug Law Institute’s annual enforcement conference in Washington, DC, CBER Office of Compliance and Biologics Quality director Melissa Mendoza offered insight into the Center's compliance priorities, facility-inspection expectations, and enforcement trends. She also previewed the agency’s new “FDA Pre-Check” program aimed at strengthening domestic manufacturing, and provided updates on several high-profile legal and oversight actions.

Mendoza said the ongoing public availability of CRLs has brought increased scrutiny to the manufacturing deficiencies that frequently lead FDA to reject BLA submissions. CBER’s pre-approval inspection program often finds that listed facilities are simply not ready — despite sponsors checking “yes” to the question on FDA Form 356h asking whether sites are inspection-ready.

“Our reviewers call to schedule inspections and are told the facility needs more time—or would prefer inspection closer to the decision date,” she said. “That seriously disadvantages the applicant and may set them up for failure.” The result: applicants have little or no time to correct deficiencies before the user fee review action deadline. Mendoza reiterated CBER’s long-standing expectation that all pre-approval inspections occur no later than mid-cycle, not late in the review. “Do not rush to market if your facility is not ready,” she warned.

Mendoza said contract manufacturing organizations (CMOs) are a persistent source of unanticipated delays and CRL deficiencies. “We often see sponsors caught off guard when their contract manufacturers are not ready,” she said. Problems include insufficiently trained operators, ongoing staff onboarding during the BLA review, inconsistency between redundant manufacturing sites, and quality-system immaturity.

Because CMOs “can make all of the difference in product quality,” she urged sponsors to maintain real-time communication with contract manufacturers and to examine systemic issues — not just fix isolated observations. Mature organizations, she said, “look holistically at their operations.”

Mendoza listed several inspection-readiness expectations:

Do:

  • Use pre-BLA and Type C meetings to obtain detailed facility and GMP feedback.
  • Maintain a robust quality-control unit and demonstrate manufacturing consistency.
  • Review and address findings from foreign regulatory audits.
  • Listen to on-the-ground facility staff.

Don’t:

  • Assume a facility is inspection-ready because it is new, state-of-the-art, or has (XXX a long XXX) long operating history.
  • Dispute observable issues during inspections.
  • Submit an application when facility shutdowns or manufacturing transitions are underway.

Mendoza also provided a brief update on FDA’s new Pre-Check initiative, which aims to accelerate domestic pharmaceutical facility construction and bolster supply-chain resilience. The program, aligned with a recent White House executive order, seeks to improve regulatory predictability and remove unnecessary requirements. CBER is reviewing comments submitted to the FDA’s public docket after a September meeting, she said. More details will be released in the coming months.

Turning to enforcement, Mendoza highlighted recent Warning Letters and compliance initiatives. She said CBER issued 25 Warning Letters in FY 2025, roughly 60% involving unapproved regenerative medicine products, including birth-tissue-derived cellular therapies.

Other enforcement categories included:

  • Unapproved HIV test kits and collection devices
  • False or misleading direct-to-consumer advertising
  • Allergenic products and amniotic fluid manufactured in violation of GMP
  • Blood components, immune globulin, and at least one vaccine with compliance issues
  • Improperly regulated autohemotherapy devices
  • Fecal microbiota transplantation products
  • Cell and tiwwue product violations across both Part 1271 tissue products and products regulated as drugs/biologics

Mendoza also noted stepped-up enforcement in bioresearch monitoring, including letters to clinical investigators for human-subject protection violations, and renewed efforts to bring sponsors into compliance with ClinicalTrials.gov reporting.

Additionally, Mendoza said last year’s “unified compliance” reorganization, which shifted biologics compliance personnel from the Office of Regulatory Affairs into CBER, has significantly accelerated compliance actions. “It now takes us one-third of the time to issue Warning Letters, from inspection closeout to issuance, compared with before,” she said. CBER has also begun using a risk-based domestic and foreign site-selection process, consistent with Section 510(h) of the FD&C Act. Mendoza said coordination with the Office of Inspections and Investigations is “instrumental,” and foreign inspections are now driven by FDA’s initiative to increase unannounced foreign inspections.

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