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WARNING LETTER

UCSF Radiopharmaceutical Facility MARCS-CMS 719568 —

Delivery Method:
Via Electronic Mail - Return Receipt Requested
Reference #:
320-26-62
Product:
Drugs
Recipient:
Recipient Name
Dr. Robin C. Cumming
Recipient Title
Director, Radiopharmaceutical Facility
UCSF Radiopharmaceutical Facility

185 Berry St. Ste. 350
San Francisco, CA 94107-9107
United States

Issuing Office:
Center for Drug Evaluation and Research (CDER)

United States

Warning Letter 320-26-62

April 13, 2026

Dear Dr. Cumming:

The United States Food and Drug Administration (FDA) inspected your drug manufacturing facility, UCSF Radiopharmaceutical Facility, FEI 3005947301, at 185 Berry St. Ste. 350, San Francisco, from July 21 to 24, 2025.

This warning letter summarizes significant violations of Current Good Manufacturing Practice (CGMP) regulations for (b)(4) drugs. See Title 21 Code of Federal Regulations (CFR), part (b)(4) (21 CFR part (b)(4)).

Because your methods, facilities, or controls for manufacturing, processing, packaging, or holding do not conform to CGMP, your (b)(4) drug products are adulterated within the meaning of section 501(a)(2)(B) of the Federal Food, Drug, and Cosmetic Act (FD&C Act), 21 U.S.C. 351(a)(2)(B).

We reviewed your August 14, 2025, response to our Form FDA 483 in detail and acknowledge receipt of your subsequent correspondence.

During our inspection, our investigators observed specific violations including, but not limited to, the following.

1. Your firm failed to conduct adequate investigations and take appropriate corrective action when a failure of a production batch or any component of the batch failed to meet any of its specifications. (21 CFR (b)(4)).

You manufacture (b)(4) drug products for (b)(4) administration. Your investigations into multiple failing sterility test results were inadequate. From 2022 to 2023, you initiated multiple investigations into sterility test failures for batches of (b)(4) injection and concluded that the probable root cause was contamination by the operator during sampling of the finished product vial. However, your investigations did not adequately support this root cause.

For example, you opened a sterility failure investigation on April 3, 2023, after your analyst reported turbidity in the (b)(4) tube during incubation of your sterility sample for a batch of (b)(4) for injection. The recovered microorganism was identified as Bacillus species, a gram-positive spore-forming bacterium. Although no conclusive laboratory testing errors were found, your investigation postulated that the batch of (b)(4) was contaminated with the bacteria during sterility testing. You invalidated the sterility test result based on your flawed assumption that the organism also should have grown in the (b)(4) tube.

Your firm failed to thoroughly evaluate whether this and other batch sterility test failures were caused by deficient aseptic manufacturing practices. Notably, your facility has experienced multiple recoveries of spore-forming organisms in sterility samples and production environments.

You also investigated deviations from sterility test procedures in which your analyst discarded sterility samples for at least two (b)(4) batches on (b)(4) of incubation instead of day 14 as specified in USP <71>. Your investigation stated that “it is highly unlikely that bacterial growths would occur on the 14th day of incubation. . . it is more likely that growth would appear before (b)(4) of testing.” However, your firm failed to note that slow growing or injured microorganisms may become detectable at the end of the incubation period.

In your response, you indicate that the sterility failures were false positives and that root causes were described in reports for each incident. You also state that you updated your sample labeling and identification procedures to prevent discarding of sterility samples before the required incubation period.

Your response is inadequate because there remains a lack of compelling evidence that the sterility failures were attributable to laboratory contamination. Your belief that (b)(4) media must both exhibit growth and if they do not, the test should be considered a false positive, fails to recognize that each medium possesses unique sensitivities, limitations, and growth capabilities. It is not appropriate to require growth in both media to establish a positive sterility failure for a sterile drug product batch.

Furthermore, you did not sufficiently detail improvements to ensure that any future sterility positive is investigated properly and includes a comprehensive evaluation of potential manufacturing root causes. Your response also lacks adequate provisions for thoroughly reviewing your sterility test method to minimize potential for false positives.

(b)(4) drug products have short expiry periods. Consequently, (b)(4) drug products are released and administered before the results of batch specific sterility testing and environmental monitoring (EM) are known. A robust ongoing EM program is essential to detect and respond to potential product contamination hazards in your manufacturing environment in a timely manner. Loss of environmental control in an aseptic manufacturing facility can ultimately pose a serious hazard to patients.

In response to this letter, provide the following:

  • A comprehensive assessment of your overall system for investigating deviations, discrepancies, complaints, out-of-limit (OOL) and out-of-specification (OOS) results, and failures. Provide a detailed action plan to remediate this system. Your action plan should include, but not be limited to, significant improvements in investigation competencies, scope determination, root cause evaluation, corrective action and preventive action (CAPA) effectiveness, quality unit oversight, and written procedures. Address how your firm will ensure all phases of investigations are appropriately conducted.
  • A retrospective, independent review of all invalidated sterility test results for U.S. products for the last three years from the initial date of inspection and a report summarizing the findings of the analysis, including the following for each sterility test:
    o Determine whether the scientific justification and evidence relating to the invalidated sterility test result conclusively or inconclusively demonstrates causative laboratory error.
    o For investigations that conclusively establish laboratory root cause, provide rationale and ensure that all other laboratory methods vulnerable to the same or similar root cause are identified for remediation.
    o For all sterility test results found by the retrospective review to have an inconclusive or no root cause identified in the laboratory, include a thorough review of production (e.g., batch manufacturing records, adequacy of the manufacturing steps, suitability of equipment/facilities, variability of raw materials, process capability, deviation history, complaint history, batch failure history). Provide a summary of potential manufacturing root causes for each investigation, and any manufacturing operation improvements.
    o Also, the independent, third-party review and CAPA plan should identify significant improvements to your sterility testing method that will better ensure minimization of false positives.

2. Your firm failed to follow written quality assurance procedures. (21 CFR (b)(4)).

You lacked investigations or failed to ensure their timely completion.

Your quality unit (QU) did not investigate adverse EM trends in your production areas as required by your standard operating procedure (SOP), SOP Q043 “Laminar Flow Hood Environmental Monitoring.” Specifically, in 2025, multiple EM results fell outside your action limit, but you failed to launch investigations to evaluate the adverse trends.

Additionally, your procedure required investigations to be completed within (b)(4). However, our review found systemic failures to meet this timeframe. Numerous investigations remained open for more than a year. For example, two investigations remained open for over 1000 days.

In your response, you acknowledge that you failed to follow your procedures for conducting environmental trending investigations. You state that you will perform retrospective investigations, create a new procedure for sterility failures and OOL investigations, and hire a Document Control Manager to oversee quality-related activities.

Your response is inadequate because it fails to propose a comprehensive CAPA plan to address systemic deficiencies in your investigation program. Furthermore, it lacks an analysis of the quality assurance oversight failures that allowed these deficiencies to occur and persist.

In response to this letter, provide the following:

  • All EM data and personnel monitoring data from June 2023 to present (preferably in a spreadsheet tabular format). Include pertinent details such as sample location, date and time of collection, and colony forming unit (CFU) counts. For each recovery, describe the microbial differentiation performed by the laboratory (gram stain result, color, colony morphology description, genus or species-level identification).
  • Your revised EM SOP detailing ISO 5 (b)(4) monitoring during production and requiring identification of all isolates recovered during environmental and personnel monitoring. In addition to your current action limits, confirm that you have established an appropriate limit with associated procedures that ensure evaluation and investigation of such recoveries.
  • A comprehensive assessment and remediation plan to ensure your QU is given the authority and resources to effectively function. The assessment should also include, but not be limited to:
    o A determination of whether procedures used by your firm are robust and appropriate
    o Provisions for QU oversight throughout your operations to evaluate adherence to appropriate practices
    o A complete and final review of each batch and its related information before the QU disposition decision
    o Oversight and approval of investigations and discharging of all other QU duties to ensure identity, strength, quality, and purity of all products
    o Also describe how top management supports quality assurance and reliable operations, including, but not limited to, timely provision of resources to proactively address emerging manufacturing/quality issues and to assure a continuing state of control

3. Procedures to ensure that all equipment is clean, suitable for its intended purposes, properly installed, maintained, and capable of repeatedly producing valid results, are not adequately followed. (21 CFR (b)(4)).

Your procedures lack sufficient details to ensure that you adequately control and monitor your equipment for aseptic conditions. During our inspection, investigators observed your technician performing contact plating of the ISO 7 area of the (b)(4) immediately after disinfection of surfaces with (b)(4), a practice which is likely to inhibit microbial growth on the sampling media and produce false negative results. Additionally, you lacked EM of the ISO 5 area of the (b)(4) where aseptic manipulations of sterile (b)(4) drug products occur (b)(4). An effective environmental monitoring program, with samples that appropriately represent production conditions, is essential for detecting microbial contamination in critical areas and triggering prompt actions to maintain a state of control.

In your response, you explain that contact plating is performed in the ISO 7 area to establish cleaning efficacy prior to production, and that you use air settle plates for EM in the ISO 7 area during production, as there are no opportunities to sample inside the (b)(4) after (b)(4). You commit to updating your disinfection procedures to include allowing disinfectants to fully dry before contact plating. You also commit to performing EM of the ISO 5 area where quality control and sterility samples are withdrawn from the finished product vial within the (b)(4).

Your response is inadequate. Although spore-forming microbes were identified in several instances, you did not provide evidence that you comprehensively evaluated efficacy of disinfection procedures (e.g., sufficiency of methods, frequency of use, before handling of material transfers), in response to these events. Furthermore, you did not provide an assessment of how the lack of sufficient EM data within the (b)(4) ISO 5 and ISO 7 areas impacts the ability to meaningfully identify environmental trends as part of your root cause determination of sterility failures. Vigilant and responsive EM programs should be designed to provide meaningful information on the state of control of your aseptic processing environment and ancillary classified areas.

In response to this letter, provide the following:

  • Your CAPA plan to implement routine, vigilant operations management oversight of facilities and equipment. This plan should ensure, among other things, prompt detection of equipment/facilities performance issues, effective execution of repairs, adherence to appropriate preventive maintenance schedules, timely technological upgrades to the equipment/facility infrastructure, and improved systems for ongoing management review.
  • An independent assessment of your EM program including, but not limited to, establishing appropriate limits, sampling locations and frequencies (including in ISO 5 environment), investigating deviations, and trend analysis, and a comprehensive CAPA plan.
  • A CAPA plan, based on the retrospective assessment of your cleaning and disinfection program, that includes appropriate remediations to your cleaning and disinfection processes and practices, and timelines for completion. Provide a detailed summary of vulnerabilities in your process for lifecycle management of equipment cleaning and disinfection. Describe improvements to your cleaning and disinfection program, including enhancements to cleaning effectiveness, improved ongoing verification of proper cleaning and disinfection execution for all products and equipment, and all other needed remediations.

Guidance on (b)(4) Drugs

See FDA’s guidance document (b)(4) to help you meet the CGMP requirements when manufacturing (b)(4) drugs, at (b)(4). This guidance document also references FDA’s guidance document Sterile Drug Products Produced by Aseptic Processing—Current Good Manufacturing Practice with additional concepts and expectations that may apply to (b)(4) drug manufacturing, at https://www.fda.gov/regulatory-information/search-fda-guidance-documents/sterile-drug-products-produced-aseptic-processing-current-good-manufacturing-practice.

CGMP Consultant Recommended

Based upon the nature of the violations we identified at your firm, we strongly recommend engaging a consultant qualified to evaluate your operations to assist your firm in meeting CGMP requirements. Your use of a consultant does not relieve your firm’s obligation to comply with CGMP. Your firm’s executive management remains responsible for resolving all deficiencies and systemic flaws to ensure ongoing CGMP compliance.

Field Alert Reporting

Your firm failed to submit Field Alert Reports to FDA in compliance with 21 C.F.R. 314.81(b)(1)(ii), as required by section 505(k) of the FD&C Act [21 U.S.C. 355(k)] upon discovery of a product quality defect. An applicant is required to submit, within three working days of receipt, information concerning any bacteriological contamination or any significant chemical, physical, or other change or deterioration in the distributed drug product, or any failure of one or more distributed batches of drug product to meet the specifications established for it in the application.

The intent of the 21 CFR 314.81(b)(1) regulation is to establish an early warning system so that significant problems are brought to the Agency’s attention by applicant holders to prevent potential safety hazards from drug products already in distribution.

Conclusion

The violations cited in this letter are not intended to be an all-inclusive list of violations that exist at your facility. You are responsible for investigating and determining the causes of any violations and for preventing their recurrence or the occurrence of other violations.

If you are considering an action that is likely to lead to a disruption in the supply of drugs produced at your facility, FDA requests that you contact CDER’s Drug Shortages Staff immediately, at drugshortages@fda.hhs.gov, so that FDA can work with you on the most effective way to bring your operations into compliance with the law. Contacting the Drug Shortages Staff also allows you to meet any obligations you may have to report discontinuances or interruptions in your drug manufacture under 21 U.S.C. 356C(b). This also allows FDA to consider, as soon as possible, what actions, if any, may be needed to avoid shortages and protect the health of patients who depend on your products.

Correct any violations promptly. Failure to promptly and adequately address this matter may result in regulatory or legal action without further notice including, without limitation, seizure and injunction. Unresolved violations may also prevent other Federal agencies from awarding contracts.

Failure to address violations may also cause FDA to withhold issuance of Export Certificates. FDA may withhold approval of new applications or supplements listing your firm as a drug manufacturer until any violations are completely addressed and we confirm your compliance with CGMP. We may re-inspect to verify that you have completed corrective actions to address any violations.

This letter notifies you of our findings and provides you an opportunity to address the above deficiencies. After you receive this letter, respond to this office in writing within 15 working days.1 Specify what you have done to address any violations and to prevent their recurrence. In response to this letter, you may provide additional information for our consideration as we continue to assess your activities and practices. If you cannot complete corrective actions within 15 working days, state your reasons for delay and your schedule for completion.

Send your electronic reply to CDER-OC-OMQ-Communications@fda.hhs.gov. Identify your response with FEI 3005947301 and ATTN: Christopher Keating.

Sincerely,
/S/

Francis Godwin
Director
Office of Manufacturing Quality
Office of Compliance
Center for Drug Evaluation and Research

________________

1 Under program enhancements for the Generic Drug User Fee Amendments (GDUFA) reauthorization for fiscal years (FYs) 2023-2027, also known as the GDUFA III Commitment Letter, your facility may be eligible for a Post-Warning Letter Meeting to obtain preliminary feedback from FDA on the adequacy and completeness of your corrective action plans.

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