FDA Warning Letter Breakdown: 503B Failures, Insanitary Aseptic Practices, and Weak Investigations at a Sterile Outsourcing Facility
A quick case study in how weak aseptic discipline and shallow investigations unravel 503B protections.
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On October 10, 2025, the FDA’s CDER issued a warning letter to a registered 503B outsourcing facility in Brooksville, Florida, following an inspection from March 25 to April 4, 2025.
The firm has been registered as a 503B outsourcing facility since 2020. The FDA’s investigator concluded that the firm:
Failed to meet key conditions of section 503B, including labeling and adverse event reporting;
Produced drugs under insanitary conditions, putting patients at risk; and
Violated multiple Part 211 CGMP requirements, particularly around aseptic processing, environmental monitoring, and investigations.
The FDA reviewed the firm’s response to the Form 483 and found parts of it either undocumented or plainly deficient. The letter ends with a strong recommendation for a comprehensive assessment of operations with the help of a third-party sterile manufacturing expert.
Given the FDA’s recent focus on 503Bs with the explosion of popularity in direct-to-consumer compounded drugs, and our own focus on helping these firms, let’s break this one down.
503B conditions: labeling and adverse event reporting gaps
The FDA starts by reminding the firm (and those reading the letter) what a 503B outsourcing facility is: a single-site facility that compounds sterile drugs, registers as an outsourcing facility, and complies with all section 503B requirements, including 210/211 CGMP, insanitary condition provisions, labeling conditions, and registration/reporting obligations.
Two specific 503B failures are highlighted:
1. Labeling deficiencies on compounded products
The FDA notes that some products (specifically Prednisolone/Moxifloxacin HCl/Bromfenac PF Sterile Ophthalmic Solution and Prednisolone/Moxifloxacin HCl PF Sterile Ophthalmic Solution) did not include the established name of the drug on the labeling.
Under section 503B(a)(10), certain labeling information must appear for a drug to qualify for 503B exemptions. Missing established names is one of the explicit examples the FDA uses here.
2. Adverse event reporting procedures not aligned with 21 CFR 310.305
The firm is required to submit adverse event reports in accordance with the content and format requirements under 21 CFR 310.305. The FDA states the firm’s procedures were inadequate, highlighting a specific omission: the written definition of a “serious” adverse event does not include the language about “important medical events” that may not involve death, life-threatening events, or hospitalization but still jeopardize patients or require intervention to prevent those outcomes.
The FDA quotes the missing portion from 21 CFR 310.305(b) directly in the letter.
Because not all 503B conditions are met, FDA explicitly states the firm’s compounded products do not qualify for:
Exemption from the new drug approval requirement (section 505);
Exemption from adequate directions for use (section 502(f)(1)); and
Exemption from DSCSA requirements (section 582).
Those products are therefore treated as unapproved, misbranded drugs subject to full FDCA obligations.
Ask yourself (the 503B outsourcing facilities among us):
Do your labels for compounded products include every 503B-required element, including the established name of the drug?
Does your adverse event SOP fully reproduce or reference the 21 CFR 310.305 definition of “serious” adverse drug experience, including “important medical events”?
Can you show that adverse event reports are submitted in the required format and frequency, tied to your 503B reporting obligations?
Insanitary conditions and aseptic technique failures
The FDA explicitly finds that drug products intended or expected to be sterile were prepared, packed, or held under insanitary conditions, making them adulterated under section 501(a)(2)(A).
The examples center on basic aseptic behavior and airflow control:
Operator arms resting on work surfaces. An operator rested their arms on the work surface of the hood during aseptic production. FDA notes this can introduce contamination into the ISO work area.
Disruption of “first air” by operator movements. Aseptic manipulations were conducted in a way that disrupted the “first air” in the ISO area. FDA cites failure to limit unnecessary movement and failure to use mindful, slow, deliberate movements within the laminar flow hoods and cleanroom.
Inadequate smoke studies under dynamic conditions. The firm failed to perform adequate smoke studies under dynamic conditions to demonstrate unidirectional airflow in the ISO area. Without these studies, the FDA concludes that products may be produced in an environment that does not provide adequate protection against contamination.
To be clear, these are foundational aseptic operations issues. The FDA is not arguing about advanced sterility assurance strategy here. It’s calling out basic body positioning, movement control, and airflow visualization.
Ask yourself (just about any sterile operations):
Are your operators explicitly trained and routinely observed to avoid resting any part of their body on work surfaces in ISO areas?
Do you have documented expectations and observations around slow, deliberate movement to protect first air?
Do your smoke studies reflect real operations (dynamic conditions, realistic equipment and materials in place), and do the videos clearly show unidirectional airflow sweeping away from critical sites?
CGMP violations (production controls, aseptic process validation, environmental monitoring, and investigations)
In addition to insanitary conditions, the FDA cites multiple 21 CFR Part 211 violations causing adulteration under section 501(a)(2)(B):
Production and process control procedures (21 CFR 211.100(a)). FDA states the firm failed to establish adequate written procedures “designed to assure that the drug products you manufacture have the identity, strength, quality, and purity they purport or are represented to possess.”
Microbiological contamination controls and validation (21 CFR 211.113(b)). The firm did not follow appropriate procedures to prevent microbiological contamination of sterile drugs. This includes failure to validate all aseptic and sterilization processes.
Environmental monitoring (21 CFR 211.42(c)(10)(iv)). The FDA states the firm failed to establish an adequate system for monitoring environmental conditions in aseptic processing areas.
Investigations of discrepancies (21 CFR 211.192). The firm failed to thoroughly investigate unexplained discrepancies or batch failures—even when batches had already been distributed.
The FDA reviewed PQ Pharmacy’s response and highlighted both missing documentation and substantive gaps:
No scientific justification for the choice of light intensity used during visual inspection of sterile products.
No training and qualification records for personnel performing particulate and defect inspection.
No hold-time studies and incomplete production controls. (The firm attempted to mitigate certain risks with media fills and other measures, but FDA states this is not a substitute for hold-time studies.)
Weak and incomplete investigations (211.192). DA notes that written records of investigations often lack conclusions and follow-up. Investigations were not expanded to other products using the same lots of bulk bags, syringes, or other components. While the firm claims to have reviewed other lots, deviation reports don’t list the specific lots evaluated. The FDA states that relying only on trending is not sufficient to define the investigation scope.
Smoke studies still show airflow problems. The FDA acknowledges that updated smoke studies now include dynamic operations like capping and crimping, however:
Smoke arches past rows of vials and exits the front of the hood, indicating disrupted laminar flow across the work surface.
Objects such as sampling plates and a sampler are placed in front of the back-hood ventilation, creating barriers to the intended unidirectional flow.
Ask yourself:
Do your SOPs explicitly require hold-time studies for bulk sterile product, including assessment of sterility, degradation, and container closure integrity throughout the hold period?
When you detect particulates or contamination, do you:
Trigger a clearly defined investigation path;
Map potentially affected lots, products, and components;
Examine retained samples; and
Engage with component manufacturers when a component-related cause is suspected?
Are your deviation classifications (e.g., “Critical”) tied to objective, risk-based criteria, including contamination and reprocessing events?
When smoke studies reveal airflow anomalies, do you redesign equipment layout and technique to eliminate obstructions, rather than just documenting the issue?
Key takeaways and overall lessons
Staying strictly with what the letter says, a few lessons are clear:
503B status is conditional, not permanent. Registration is only one part of being a 503B facility. If your labeling and adverse event reporting procedures do not meet 503B requirements, your products immediately lose their exemptions and are treated as unapproved, misbranded drugs.
Aseptic behavior and airflow visualization are front-line issues. Resting arms on work surfaces, unnecessary movement in ISO areas, and inadequate dynamic smoke studies are enough for the FDA to call your aseptic environment insanitary (even before sterility test failures).
