3D Imaging Drug Design and Development LLC

The United States Food and Drug Administration (FDA) inspected your drug manufacturing facility, 3D Imaging Drug Design and Development LLC, FEI 3009143510, at 9015 Carti Way, Little Rock, from June 9 to 13, 2025.

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).

In addition, we reviewed your firm’s drug listing submissions in FDA’s electronic Drug Registration and Listing System (eDRLS) and found that you failed to update the listing for your PET human prescription drug product, Fludeoxyglucose F18 (NDC 76451-118), as required under section 510(j) of the FD&C Act (21 U.S.C. 360(j)) and 21 CFR part 207.

Thus, Fludeoxyglucose F18 is not properly listed, and your firm has not fulfilled its listing obligations under 510(j) of the FD&C Act (21 U.S.C. 360(j)) and 21 CFR 207, which is prohibited under section 301(p) of the FD&C Act (21 U.S.C. 331(p)). This violation is described in more detail below.

We reviewed your June 30, 2025, response to our Form FDA 483 in detail and acknowledge receipt of your subsequent correspondence.

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

1. Your facilities are not adequate to ensure the prevention of contamination of equipment or product by substances, personnel, or environmental conditions that could reasonably be expected to have an adverse effect on product quality. 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(a) and (b)).

Facility Suitability

You failed to ensure that your facility is adequately designed and controlled to prevent contamination of the sterile injectable PET drugs you manufacture. For example, our investigator observed your operator making aseptic connections in an open benchtop area, without adequate aseptic environmental conditions. Furthermore, our investigator observed that Hot Cell #(b)(4), which is used to manufacture Fludeoxyglucose F-18 (FDG), was in a poor state of repair, with rust on the manipulator arms and with visible residue on surfaces near where the finished product is filtered into sterile vials.

In your response, you state that you made facility and equipment repairs, including removal of rust and replacement of the chipped lead shielding in your hot cell. Your response is inadequate because you do not evaluate your facility, process, and equipment for potential routes of contamination or address how you will improve your process to ensure that your product is properly protected from the environment during aseptic connections.

Appropriate aseptic environments should be used for critical aseptic manipulation in the production and testing of PET drugs.

Environmental Monitoring

You failed to establish and follow adequate testing procedures for environmental monitoring (EM) for your aseptic manufacturing area. For example, your Hot Cell #(b)(4), where the FDG drug product is filtered into the final product vials, is not monitored. Further, the alert and action levels that you established in your standard operating procedure (“SOP for Environmental Monitoring of Hot Cells”) for EM are not appropriate. For surface samples taken in your hot cell, your procedure does not require an investigation unless (b)(4) or more colony-forming units are recovered from a single sample. Your high action levels allow for an unacceptable risk of contamination to your product.

In your response, you indicate that you lack an understanding of where the environmental monitoring should occur, and that you will update your EM to include a location “adjacent to the sterile closure.” Your response is inadequate because you do not address how you will determine the appropriate sampling location and frequency for EM.

PET drug products have short expiry periods. Thus, your PET drug products are released and administered before the results of batch specific sterility testing and EM are known. Therefore, adequate microbiological monitoring of the aseptic environment is essential during critical aseptic manipulation. A vigilant, 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:

A comprehensive risk assessment of all contamination hazards with respect to your aseptic processes, equipment, and facilities, including an independent assessment that includes but is not limited to:o All human interactions within the ISO (b)(4) areao Equipment placement and ergonomicso Air quality in the ISO (b)(4) area and surrounding roomo Facility layouto Personnel flows and material flows (throughout all rooms used to conduct and support sterile operations)

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.

Your updated procedure(s) demonstrating that aseptic connections will be conducted in an appropriate environment (e.g., ISO (b)(4) aseptic workstation).

An independent assessment of your EM program, including but not limited to establishing appropriate limits, sampling locations and frequencies, investigating deviations, and trend analysis, and a comprehensive corrective action and preventive action plan.

Your action levels for ISO (b)(4) surfaces, air, and operator gloves, and revised procedures that describe the appropriate response to contamination in critical environments.

You failed to ensure that your operators are appropriately gowned to adequately protect the sterile injectable PET drugs you manufacture. For example, our investigator observed exposed skin and hair on your operator during the manufacturing of FDG lot (b)(4). The operators’ skin on their arms was exposed while they were setting up production in an open benchtop area of the room (i.e. with inadequate aseptic environmental conditions). The operators’ skin was also exposed while leaning into Hot Cell #(b)(4) to set up for product (b)(4) into sterile vials. Additionally, another operator was observed reaching into the ISO (b)(4) laminar flow hood with exposed skin on the operator’s arms and face while performing sterility testing for FDG lots (b)(4) and (b)(4).

Furthermore, you failed to adequately requalify two of the (b)(4) operators at least annually by conducting a media fill to assess their aseptic processing technique. For example, one of your operators had not been requalified to perform PET drug manufacturing using process simulations (media fills) since April 2021. However, the operator manufactured FDG as recently as June 2025.

In your response, you indicate that the two operators were removed from production and a media fill was initiated. However, your response is inadequate because you do not provide a retrospective assessment of the potential impact to drug products manufactured from 2021 to present. Your response is also inadequate because you do not comprehensively address how you will ensure that your gowning program is adequate, including whether appropriate gowning will be used.

Adequate gowning is an essential part of environmental control because gowns provide a barrier to prevent operators from contaminating the drug product. Personnel should be adequately trained and qualified to ensure their competence to perform aseptic processing of PET drugs.

Media fills should simulate the aseptic production process, including but not limited to the aseptic assembly of the container/closure system through filling of the PET drug into final containers. Operators should be requalified annually by conducting one media fill run. See FDA’s guidance document Media Fills for Validation of Aseptic Preparations for Positron Emission Tomography (PET) Drugs at https://www.fda.gov/media/81974/download.

In response to this letter, provide:

A remediation plan that better assures ongoing management oversight throughout the manufacturing lifecycle of all drug products. Provide a more data-driven and scientifically sound program that identifies sources of process variability and assures that manufacturing operations meet appropriate parameters and quality standards. This includes but is not limited to evaluating suitability of equipment for its intended use, ensuring quality of input materials, determining the capability and reliability of each manufacturing process step and its controls, and vigilant ongoing monitoring of process performance and product quality.

A comprehensive assessment of your gowning program, including but not limited to how you will establish adequate gowning.

The report and results for the media fill initiated on June 16, 2025, and any subsequent media fills conducted.

A comprehensive assessment of your media fill procedure, including but not limited to how you will ensure that operators are requalified annually.

You failed to establish and follow adequate testing procedures for sterility testing of your sterile injectable PET drugs. For example, our investigator observed your operator performing sterility testing using poor aseptic technique, including opening sterile components outside of the ISO (b)(4) laminar flow hood before use. Also, our investigator observed your chemist vigorously shaking the sterility test sample tubes before reading the results. Shaking the sterility test sample tubes may mask the test results and may impact a person’s ability to visually detect turbidity, visible colonies, or other evidence of microorganisms.

In your response, you indicate that you updated your sterility testing procedure. However, your response is inadequate because it lacks information about how you will ensure that your procedures are sufficiently detailed for operators to follow and how you will ensure that sterility testing is adequately performed.

Testing is a critical control that provides assurance that your PET drug products are sterile and therefore suitable for their intended use. It is important that you follow established, appropriate procedures to ensure that your sterility testing can detect the presence of microorganisms.

In response to this letter, provide:

A comprehensive assessment of your laboratory practices, procedures, methods, equipment, documentation, and analyst competencies. Based on this review, provide a detailed plan to remediate and evaluate the effectiveness of your laboratory system.

A comprehensive assessment of your sterility testing program, including but not limited to material flow and environmental monitoring.

A comprehensive review of your sterility testing procedure relative to the expectations in the United States Pharmacopeia (USP) General Chapter <71,> Sterility Tests.

Your most recent static and dynamic smoke studies performed for the laminar flow hood.

Section 510(j) of the FD&C Act (21 U.S.C. 360(j)) and 21 CFR part 207 set forth the requirements for the listing of drugs. Under 21 CFR 207.57(b), registrants are required to update drug listing information twice each year, in June and December. Under 21 CFR 207.57(b)(2), registrants may satisfy the listing update requirement with respect to unchanged listing information by making a single “no changes” certification during the October 1 through December 31 annual registration period. If the drug listing data is not updated or certified, the outdated listing data will get inactivated at the next scheduled FDA inactivation period.1 You failed to update or certify Fludeoxyglucose F18 as required.

Therefore, Fludeoxyglucose F18 is not properly listed under section 510(j) of the FD&C Act. Failure to properly list a drug in accordance with 510(j) of the FD&C Act is prohibited under section 301(p) of the FD&C Act (21 U.S.C. 331(p)).

Complete, accurate, and up-to-date establishment registration and drug listing information is essential to promote and protect patient safety. FDA relies on establishment registration and drug listing information for several key programs, including drug establishment inspections, supply-chain security, and postmarket surveillance. Establishment registration and drug listing information is also widely used outside FDA for purposes such as electronic prescribing and electronic health records, insurance reimbursement, and patient education.

In addition, we note that your drug listings for Ammonia N 13 (NDC 76451-013) and Sodium Fluoride F-18 (NDC 76451-018) also have not been updated or certified. Please update the listing information for these drugs to reflect their current status. If you no longer manufacture and distribute these drugs, then the drugs must be discontinued by adding an end marketing date. Please be aware that a manual override may be required for certain types of revisions made to an existing drug listing file. If you receive a validation error or have any questions regarding your drug listings, please contact us at eDRLS@fda.hhs.gov for further assistance.

It is your responsibility to ensure that all drugs manufactured at your establishment comply with all establishment registration and drug listing requirements under section 510 of the FD&C Act, 21 U.S.C. 360, 21 CFR part 207, and all other applicable FDA regulations. Registration and listing information and instructions on how to properly register an establishment or submit drug listings can be found at Electronic Drug Registration and Listing Instructions.

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.

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.

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 days2. 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 3009143510 and ATTN: Lynnsey Renn.