When "Undetermined" is not an Answer: What two FDA Warning Letters Show about Root Cause Analysis and CAPA

Two recent U.S. Food and Drug Administration (FDA) Warning Letters highlight a recurring weakness in pharmaceutical quality systems: treating an investigation as complete before the organisation knows what really happened, assessed the full product risk, and implemented actions capable of preventing recurrence.

The letters, addressed to Fresenius Medical Care AG & Co. KGaA in Germany and Jabil Inc. in the US, both cite failures to thoroughly investigate unexplained discrepancies, batch failures, or failures of components to meet specifications under 21 CFR 211.192. In both cases, FDA also criticised the associated corrective and preventive actions (CAPA) as inadequate. The underlying events were different; leaking peritoneal dialysis bags in the Fresenius case and sterility and environmental-monitoring concerns in the Jabil case. But the regulatory message was consistent: a plausible explanation is not necessarily a root cause, and a procedural promise is not necessarily an effective CAPA.

Fresenius: A complaint trend, an incorrect risk assessment, and insufficient action

In its Warning Letter to Fresenius, FDA described an investigation initiated in August 2025 in response to a complaint trend involving leaking bags in a Dialysis Solution. The investigation ultimately covered 35 complaints involving approximately 156 bags from multiple batches. Fresenius attributed the leaks to "holes caused by printing."
FDA's criticism focused not only on the suspected mechanism of failure, but also on how the risk was assessed and how the investigation was translated into action. Although Fresenius's Risk Management Matrix identified the potential harm and recommended the highest severity level, the company assigned the lowest severity level and identified the potential harm as "damage of property."
FDA described several justifications cited for the earlier decision, including product labelling instructing users to inspect bags, the expectation that leaks would be readily detected before treatment, and the assumption that leaking fluid would collect in the overwrap. However, following the inspection, Fresenius reported that a reexamination of part of one batch found perforations in the primary container without substantial fluid in the overwrap. FDA said this demonstrated the error in assuming that users could consistently detect leaking units.

The safety significance described in the letter was substantial. FDA stated that the decision not to recall the affected batches exposed patients to potentially non-sterile drug products. The company reassessed the incident, decided to recall the impacted lots, and revised its procedure so that known and potential harms would be evaluated during risk assessments.
FDA nevertheless considered the response inadequate because it did not include sufficient CAPA to improve the detection of leaking units during manufacturing and prevent their release and distribution.

FDA now requested a comprehensive, independent assessment of the root causes of leaking bags including CAPA addressing the identified root causes, such as replacing the current printing technology. These requests show that FDA was not looking only for a revised complaint procedure. It expected the investigation to reach into the process, equipment, controls, and lifecycle validation supporting bag integrity.

Jabil: "Undetermined" root cause and recurring fungal recoveries

The Warning Letter to Jabil concerned its contract manufacture of sterile injectables. FDA cited an inadequately investigated sterility-test failure and recurring mold recoveries in an ISO 5 (Grade A) filling area.

The sterility-test failure

FDA stated that Jabil had identified Ustilago spermophora in the medium associated with a failed sterility test for an aseptically filled injectable product. Jabil's investigation recorded the root cause as "undetermined." FDA considered that conclusion inadequate because the investigation had not thoroughly examined possible routes by which fungi could migrate through the classified areas.

FDA specifically identified potential routes requiring evaluation, including:

• Personnel and material flow hazards;
• HVAC hazards; and
• Inadequate disinfection.

Although Jabil rejected the batch, FDA stated that the investigation did not include adequate CAPA responses. FDA acknowledged Jabil's stated intention to strengthen investigation requirements, conduct a retrospective review, and review the facility's contamination control strategy. However, FDA considered the response inadequate because it did not specifically address the sterility-failure investigation.

Environmental-monitoring action-level excursions

FDA also described several fungal recoveries associated with aseptic processing and stated that the investigation did not adequately evaluate potential root causes, including whether the mold was introduced during filling operations. The product was released without sufficient investigation.
Also for other deviations, FDA noted failures in investigations, insufficient CAPA, closed investigations without implementing robust CAPA

Jabil committed to revising procedures, implementing routine trend analysis, and strengthening investigations. FDA considered that response inadequate because Jabil continued to rely on product-impact conclusions, without sufficiently addressing contamination sources.

FDA made an important distinction in this context: procedural updates and training alone do not address systemic failures that allowed deficient investigations to persist undetected by quality-unit oversight.
FDA now requested an independent assessment of Jabil's overall system for investigating deviations, discrepancies, complaints, out-of-specification results, and failures and an independent assessment and remediation plan for the CAPA programme.

The common lesson: investigation quality determines CAPA quality

The two letters show why Root Cause Analysis (RCA) and CAPA cannot be treated as separate administrative steps. If the investigation is too narrow, the CAPA will normally be too narrow as well. If the risk assessment is wrong, the urgency and scope of containment may also be wrong.

The message for manufacturers is clear: investigate the full risk, challenge assumptions, follow recurring signals across time and systems, and implement actions that address the causal mechanism. Where the root cause is not found, the investigation must still demonstrate rigorous evaluation of plausible causes and a scientifically justified control strategy. Where CAPA is implemented, its effectiveness must be demonstrated.

Editorial note: FDA Warning Letters describe the agency's inspection findings and regulatory expectations at the time of issuance. Readers should consult the complete letters and any subsequent FDA correspondence for the current status of the matters described.