FDA 于 2026 年 10 月 22 日就 PET 药物 CGMP 违规向 Northland Nuclear Medicine, LLC 发出警告信

Delivery Method:

VIA UNITED PARCEL SERVICE WITH RETURN RECEIPT REQUESTED
VIA ELECTRONIC MAIL READ/DELIVERY RECEIPT REQUESTED

Reference #:

320-27-08

Product:

Drugs

Recipient:

Recipient Name

Nathan J. Fleck, Pharm.D.

Recipient Title

President & Owner

Northland Nuclear Medicine, LLC

1815 Michigan Ave.
Bismarck, ND 58504-6121
United States

(b)(4)

Issuing Office:

Center for Drug Evaluation and Research (CDER)

United States

October 22, 2026

WARNING LETTER
Reference number: 320-27-08

To Dr. Nathan J. Fleck:

This warning letter advises you of significant violations observed during a U.S. Food and Drug Administration (FDA) inspection of your facility. Promptly address the violations described herein without delay, including ensuring that appropriate resources are allocated to fully address the violations and prevent their recurrence. This is not intended to be an all-inclusive list of the violations that exist at your facility. It is your responsibility to ensure that your firm complies with all requirements of federal law, including FDA regulations. Failure to adequately address violations may result in regulatory or legal action without further notice including, without limitation, seizure and injunction.

FDA Inspection

Violations were observed and documented during an inspection of your drug manufacturing facility, Northland Nuclear Medicine, LLC, FDA Establishment Identifier (FEI) 3005334016, located at 1815 Michigan Ave., Bismarck, from May 26 to 29, 2026. This inspection was conducted under FDA’s statutory authority and public health responsibilities to protect the public from unsafe, ineffective, and poor quality drugs.

This warning letter summarizes significant violations of Current Good Manufacturing Practice (CGMP) regulations for positron emission tomography (PET) drugs. See Title 21 Code of Federal Regulations (CFR), part 212 (21 CFR part 212).

Because your methods, facilities, or controls for manufacturing, processing, packaging, or holding do not conform to CGMP, your PET 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 June 11, 2026, response to our Form FDA 483 in detail. Your response is inadequate because you failed to provide supporting documentation for evaluation or adequate evidence of corrective actions taken to bring your operations into compliance with CGMP.

Violations of the Federal Food, Drug, and Cosmetic Act

The following are violations observed during our inspection and review. As a reminder, this is not an all-inclusive list of violations at your facility.

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 212.20(d)).

Inadequate Investigation of Out-of-Limit Environmental Monitoring Results

Your firm failed to adequately investigate out-of-limit (OOL) environmental monitoring (EM) results, identify the root cause of recurring microbial recoveries, and implement appropriate corrective actions. EM data from March 2024 through April 2026 revealed an adverse trend with over 100 microbial recoveries from ISO 5 areas (e.g., (b)(4) and laminar airflow workstation (LAFW)), including counts of (b)(4) colony forming units (CFUs). These recoveries were not formally identified, preventing your firm from conducting adequate investigations. More than 90 ISO 5 isolates were documented as “resembles previously identified Bacillus colonies” or “resembles previously identified colonies” in lieu of formal microbial identification, with no record of which previously identified organism the colony purportedly resembled. Since December 2024, of approximately 75 ISO 5 microbial recoveries, only two were sent for formal identification. No genus or species recovered in ISO 5 areas has been recorded in your EM log since September 2025. Operator training for interpreting (b)(4) plate results consisted of a single presentation slide instructing personnel to “count CFUs and record results,” with no instruction regarding microbial identification.

Additionally, (b)(4) ISO 7 cleanroom certification results for areas surrounding your (b)(4) and LAFW revealed microbial recoveries that exceeded your action limits and were not adequately investigated. For example, a (b)(4) CFU active air recovery described as bacterial and yeast was not adequately identified because the sample plates were received with (b)(4) on the lid. For a (b)(4) CFU recovery sent for identification, (b)(4) CFU were identified as Pseudopithomyces palmicola and the remaining (b)(4) CFU were identified as Micrococcus spp. and coryneform bacillus. Investigations were not initiated. Further, your (b)(4) product review acknowledges “excess CFUs as an ongoing issue in the (b)(4) cleanroom.”

Your firm systematically failed to adequately investigate out-of-limit environmental monitoring results, to identify root causes of recurring microbial contamination in critical ISO 5 areas, and to implement effective corrective action and preventive action (CAPA).

In your response, you commit to ensuring that future microbial colony recoveries from ISO 5 areas will be properly identified and documented. Your response is inadequate because it does not include a retrospective assessment of the unidentified recoveries or an evaluation of adverse trends, does not assess the adequacy of past batch release decisions made in the absence of organism identification, and does not address the documented presence of spore-forming bacteria and fungi in your ISO-classified environments.

Environmental isolate identification data provides essential information for an investigation into routes of contamination, such as when investigating an adverse environmental control trend, media fill contamination, or a product sterility testing failure. EM should include routine identification of microorganisms to the species (or, where appropriate, genus) level, including isolates recovered from an ISO 5 environment, its surrounding cleanroom, and personnel.

It is essential that cleaning and disinfection procedures are described in sufficient detail, including the preparation, disinfectant selection, and contact time to enable reproducibility and ensure that potential contaminants are adequately removed from surfaces. The effectiveness of disinfection procedures should be evaluated through a routine EM program, and adverse trends should prompt reassessment of disinfectant selection, concentration, contact time, and application frequency.

Inadequate Investigation and CAPA for Recurring Manufacturing Deficiencies

You failed to conduct adequate effectiveness checks for CAPAs to prevent recurrence.

Multiple CAPAs for recurring low (b)(4) yields were closed without your required effectiveness checks. Yields continued to fall below your established (b)(4)% limit. No investigations were initiated for approximately (b)(4) batches manufactured between August 2024 and April 2025 that failed the (b)(4)% limit, with yields as low as (b)(4)%. Rather than identifying and correcting the root cause, you lowered the yield limit from (b)(4)% to (b)(4)%. Yields subsequently fell below your revised (b)(4)% limit. Notably, Incident Report NNM 2025 08 states, “This has been an ongoing issue now for more than a year. We are continuing to evaluate the situation in an attempt to increase yields.” The effectiveness check for that incident was marked “No” with no additional corrective action identified. You continue to manufacture your PET drug without resolving the root cause of the low yields.

PET drug producers must establish appropriate action limits for radiochemical yield and investigate and correct the root cause when those limits are exceeded. Low yields or a downward trend in yield are recognized indicators that the production process may be losing control. Lowering a yield limit to accommodate a failing process does not satisfy this requirement. Producers must maintain adequate production and process controls to ensure consistent production and must implement appropriate CAPA to prevent recurrence of nonconforming results.

In your response, you commit to retrain manufacturing personnel on effectiveness check requirements and to formally complete the incident report form. Your response is inadequate because you have not conducted a retrospective evaluation of the batches manufactured and it fails to address the root cause of the persistent low-yield problem. Additionally, your response does not address the adequacy of lowering your yield limit from (b)(4)% to (b)(4)% as a corrective measure in lieu of identifying and resolving the root cause of persistent yield failures.

To ensure proper root cause analysis and appropriate CAPA implementation, investigations must be thorough, well-documented, scientifically sound, and timely. Training alone does not address the systemic failures that allowed deficient investigations to persist undetected by quality unit (QU) oversight.

In response to this letter, provide:

• An independent, comprehensive review of your EM program to ensure vigilant, timely detection and response to potential product contamination hazards in your manufacturing environment. This assessment should include, but not be limited to:
  o establishing appropriate limits,
  o sampling methods,
  o sampling locations and frequencies,
  o trend analysis,
  o appropriate investigation of deviations and adverse trends,
  o and a comprehensive CAPA plan based on the findings of the assessment.
• A comprehensive, independent assessment of your overall system for investigating deviations, discrepancies, complaints, OOS results, OOL results, and failures. Provide a detailed action plan to remediate this system, encompassing the following:
  o staff competencies (including use of appropriate subject matter experts)
  o written procedures
  o scientific rigor and foundation
  o scope determination
  o root cause evaluations
  o CAPA effectiveness
  o quality unit lead functional roles, and oversight to ensure all phases of investigations are appropriately conducted.
  o and, based on above, detailed systemic improvements to the investigation system
• 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
  o appropriate
  o provisions for QU oversight throughout your operations to evaluate
  o 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

2. 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 212.30(b)).

Inadequate Control of Environmental Monitoring Plates

You failed to adequately control your EM contact plates used to monitor your production operations.

EM plates were stored inside a (b)(4) containing a significant amount of (b)(4) solution before and after sampling. You failed to assess the impact of this practice on microbial recovery.

(b)(4) is a (b)(4) with well-documented sporicidal activity. Exposure of EM plates to (b)(4) can kill or suppress the microorganisms these tests are designed to recover, rendering results unreliable and potentially generating false negatives.

In your response, you state that personnel have stopped spraying EM plates and that procedures have been updated accordingly. Your response is inadequate because it does not address the reliability of historical EM data collected using the compromised methodology, does not include a retrospective assessment of past EM results that were affected by (b)(4) exposure, and does not evaluate the adequacy of prior batch release decisions made in the absence of reliable environmental monitoring data.

Inadequate Airflow Visualization Studies (Smoke Studies)

Your firm failed to ensure adequate control of airflow in the ISO 5 critical aseptic processing area. Smoke studies conducted at your facility did not include a dynamic evaluation of LAFW or (b)(4) operations and therefore do not adequately demonstrate that unidirectional airflow effectively controls air quality during aseptic manufacturing.

Adequate contamination control in an aseptic PET drug manufacturing environment requires that monitoring tools, disinfection practices, and airflow qualification studies be designed and executed in a manner that meaningfully protects the sterility of the product. Compromised environmental monitoring media, inadequate airflow qualification, and failure to disinfect product-contact surfaces prior to aseptic operations collectively undermine the sterility assurance of your PET drugs.

In your response, you commit to include transfer of starting components and materials prior to mock operations going forward. Your response is inadequate because you do not address the absence of a validated, dynamic evaluation of actual LAFW and (b)(4) operations under representative conditions.

Failure to Adequately Disinfect (b)(4)

You failed to adequately disinfect the exterior surfaces of the (b)(4) prior to aseptic manufacturing operations and failed to establish written procedures for the cleaning and disinfection of (b)(4) surfaces.

In your response, you indicate that personnel were informed and retrained on the procedures for proper disinfection. Your response is inadequate because it does not establish a written disinfection procedure for the (b)(4) as a required step in your aseptic manufacturing process.

PET drug products have short expiry periods. Consequently, PET drug products are released and administered before the results of batch specific sterility testing and EM are known. Your 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. Cleaning and disinfection should be performed frequently to ensure consistent control of environmental quality.

In response to this letter, provide:

• A comprehensive CAPA, overseen by a qualified consultant, for handling microbiological sampling media to ensure robust and reliable data. Establish a system that ensures uninterrupted custody and full reconciliation of all microbiological samples, including but not limited to:
  o unique labeling of each sample
  o signatures of all staff who handle the sample
  o complete tracking of sample integrity and custody
  o date and time of each activity (e.g., sample collection, delivery, incubation, removal from incubator)
  o digital time-stamped photos of all plates
  o signatures of personnel performing reading of microbial counts
  o provisions for verifications and routine quality assurance oversight.
• Comprehensive, independent risk assessment of all contamination hazards with respect to your aseptic processes, equipment, and facilities, including but not limited to:
  o all human interactions within the ISO 5 area (e.g., risk reduction or elimination of manual interventions wherever possible)
  o equipment suitability (e.g., reliability, capability, ergonomics, placement) and sufficient cleanroom space
  o air quality in the ISO 5 area and surrounding room including, but not limited to, air volume and flow
  o facility layout
  o personnel Flow and Material Flow (movement throughout all rooms used to conduct and support sterile operations, and all material transfers)
  o disinfection practices and procedures
  o specific CAPA recommendations that will comprehensively address the design and control hazards identified in the risk assessment
• A thorough, independent evaluation of airflow unidirectionality in your aseptic process. Ensure smoke studies are conducted under dynamic conditions, with comprehensive evaluations of aseptic processing airflow unidirectionality, including the impact of aseptic interventions and surrounding cleanroom hazards. Conduct the smoke studies after you remediate your aseptic operation, using proper practices (e.g., neutrally buoyant media) to appropriately visualize airflow.
• A detailed remediation plan with timelines to address the findings of the contamination hazards risk assessment. Describe specific tangible improvements to be made to aseptic processing operation design and control at your facility and explain how this CAPA plan will robustly remediate your deficient sterile manufacturing operations. Include comprehensive changes to the design of both your aseptic processing lines and cleanrooms. Also, describe your plans for qualification and validation of your extensively remediated operations.

Repeat Violations at Facility

In a regulatory meeting held on December 13, 2023, FDA discussed similar CGMP violations. You proposed specific remediation for these violations. Repeated failures demonstrate that executive management oversight and control over the manufacture of drugs is inadequate.

Guidance on PET Drugs

See FDA’s guidance document, PET Drugs—Current Good Manufacturing Practice, to help you meet the CGMP requirements when manufacturing PET drugs, at https://www.fda.gov/media/71013/download. This guidance document also references FDA’s guidance document, Sterile Drug Products Produced by Aseptic Processing—Current Good Manufacturing Practice for additional concepts and expectations that may apply to PET drug manufacturing, at https://www.fda.gov/media/71026/download.

CGMP Consultant Recommended

Based upon the nature of the violations we identified at your firm, you should engage a consultant qualified to evaluate your operations and to assist your firm in meeting CGMP requirements. The qualified consultant should also perform a comprehensive audit of your entire operation for CGMP compliance and evaluate the completion and efficacy of your corrective actions and preventive actions before you pursue resolution of your firm’s compliance status with FDA.

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.

Conclusion

You are responsible for investigating and determining the root causes of any violations and implementing corrective and preventative measures to ensure future and sustained compliance so that these violations and any others do not occur.

Unresolved violations may 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.

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 [email protected], 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.

Send your written response to [email protected] within fifteen (15) business days of receipt of this letter. Identify your written response with FEI 3005334016 and ATTN: Compliance officer Michael Klapal in the letter or in the subject line of the email.

If you have information that you believe demonstrates that your products are not in violation of the FD&C Act and FDA regulations, include that information for our consideration.

FDA posts warning letters to www.FDA.gov.

Sincerely,
/S/

Francis Godwin
Director
Office of Manufacturing Quality
Office of Compliance
Center for Drug Evaluation and Research
U.S. Food and Drug Administration