Transforming an Academic Radiochemistry Facility for Positron Emission Tomography Drug cGMP Compliance

The consultant analyzed the BMC cGMP systems using a gap assessment checklist based on 21 CFR 212 (Supplement online: Gap analysis checklist) to record information and provide a road map identifying areas where improvements could be made in preparation for an upcoming inspection. Following this review, BMC management devised a Management Action Plan to close the gaps prior to the FDA inspection. Management monitored the project’s progress and, on completion, the operation was re-assessed to confirm that the gaps were closed. Shortly after completion of the gap closure project, the FDA contacted the BMC to schedule a pre-approval inspection. Both PET probes [¹⁸F]FDG and [¹³N]NH₃ received “recommended for approval” from the inspection with only minor FDA Form 483 observations of deficiencies issued.

The operation has since been regularly re-assessed by scheduled quality system review and internal audits to ensure continuous compliance and quality in PET drug production. Regular ongoing reassessment also includes addressing new requirements introduced since the last analysis, thus establishing a system for continuous improvement of the operation.

Environmental classification of an ISO 5 (class 100) environment for aseptic manipulation (such as product vial assembling, QC sample withdrawal, sterility test inoculation, etc.) is required by cGMP guidance from the FDA. Two laminar air flow hoods (LAFH, Type II A Biosafety Cabinet) were acquired and installed in production and QC rooms, respectively. The locations of the hoods were selected to ensure optimal workflow and minimal traffic. The LAFH installed in the production room is lead shielded for the safe handling of radioactive samples, which is considered an appropriate engineering control for the amount of radioactivity BMC handles. The lead shield minimizes the operator’s exposure when withdrawing samples for QC. It contains an integrated dose calibrator to measure End of Synthesis (EOS) dose activity. The second LAFH installed in the QC room is not shielded and is mainly used for non-radioactive operations, such as assembling product vials and inoculating sufficiently decayed QC samples into growth media for sterility testing. Both LAFHs were ISO 5 certified initially and tested thereafter for conformity every 6 months, including inflow and downflow velocity measurements, smoke test, HEPA filter integrity testing, and particle counts. Moreover, all aseptic operations were environmentally monitored by air settle plates, contact plates, and touch plates, according to the FDA PET cGMP guidance. UCLA BMC chose to perform sterility testing in-house. Although this task could be outsourced to a qualified analytical testing company, it should be noted that outsourcing brings additional expense and work auditing the company for compliance. Figure 1 illustrates the floor plan and material/personnel flow inside the BMC production/QC area.

The BMC conducted an initial PET cGMP and microbiology training for staff by external consultants, who were selected as highly regarded experts in the field. All staff demonstrated proficiency in PET cGMP and aseptic handling by passing written assessment after the training. They were also observed performing tasks by quality assurance specialists for compliance.

As advised by our quality consultant, we outlined the hierarchy of cGMP documentation to be established (Fig. 2).

The top tier documentation included a site master file and quality system manual. These top tier documents outlined the quality commitment and responsibility oversight at the BMC. The second tier documentation included detailed Quality Assurance (QA) procedures, such as a validation plan, change control, personnel training policy, finished product release, investigation of out-of-specification (OOS), out-of-trend or process deviation, product recall, complaint handling, corrective and preventive actions (CAPAs), and conditional release procedures. The third tier of documentation contained material/component specification sheets and standard operating procedures (SOPs) for manufacturing, QC testing, and equipment calibration/maintenance. The fourth tier consisted of records of performed tasks and production/QC activities.

The acceptance criteria for materials used in routine productions and quality control procedures were established and approved in written Specification Bulletins (SB). All incoming materials and components were quarantined upon receipt and underwent acceptance/rejection procedures outlined in the corresponding SBs. Subsequently, the accepted materials were affixed with acceptance labels and tracked by assigned, unique inventory tracking numbers (ITN). Any in-house prepared solutions or reagents were tracked by unique preparatory tracking numbers (PTN). BMC has an off-site material storage room in close proximity, which is equipped with a temperature-controlled freezer and refrigerator monitored by 21 CFR part 11 compliant Wi-Fi-enabled digital temperature probes. Only accepted and properly tracked materials can be brought into production/QC areas.

Process validation runs and final product stability testing were performed and documented for all PET drugs. The final products underwent stability testing at the EOS and proposed expiry time. Final product vials were stored in an upside-down fashion at room temperature to mimic the worst-case scenario during shipment. Each radiochemist passed three consecutive qualification runs and three initial media fill simulations to qualify as an operator.

Periodic QA staff meetings and QA management meetings are essential to the QA program at the BMC. These meetings are to discuss and address quality-related issues and concerns of the entire operation, including facility, equipment, materials, production, and analytical methods.

Routine facility cleaning and upkeep, equipment check, cleaning, preventive maintenance, and calibration are performed and documented at preset intervals. The environmental classifications of production area, QC area, and ISO 5 LAFH are routinely monitored and certified by an outside contract vendor.

Change controls are performed when any production or QC-related material/equipment/method change is requested. Risk assessment for the potential impact to product quality is evaluated and documented. Additional verification or validation data are generated for change control. Any material, process, and QC testing changes are filed with the FDA based on their significance categories (major, moderate, or minor).

Periodic quality indicator testing (PQIT) and annual final product stability testing are conducted as part of post marketing commitment. PQIT varies between different products, but in general, it includes radionuclide purity testing to detect long-lived radionuclide impurities, specific activity (if applicable), and other potential chemical impurities (such as 2-chloro-2-deoxy-D-glucose for [¹⁸F]FDG).

Periodic document/record review is a key component of continuous compliance. Every day, the BMC generates records such as executed batch records, material/reagent tracking, product vial assembly, production and QC raw data, etc. Periodic review adds assurance that all records are completed and filed correctly, and that SOPs contain clear instructions. At the BMC, production and QC records are usually reviewed quarterly before being archived. Quality assurance and operational procedures are reviewed every 3 years at minimum.

An internal cGMP audit is conducted annually by a qualified QA person or a contracted external consultant. Any problems or inconsistencies discovered during the audit are followed up for correction or improvement. Identified corrective or preventive actions are implemented and subsequently verified through the CAPA program at BMC.

cGMP training and radiochemist re-qualification are offered on an annual basis. Annual cGMP refresher trainings are coordinated with the clinic schedule to ensure radiochemists have undivided attention during the training. In addition, qualified radiochemists are re-qualified annually by passing one medial fill simulation to ensure proper aseptic technique.

Product batches that are out-of-specifications, out-of-trend, or with a yield that exceeds action limit mandate a full investigation. During the investigation, root cause analysis and identification, risk assessment, and corrective/preventive actions (identification/implementation/verification) are performed and documented.

Written procedures for complaint handling are established at BMC in case a drug quality or drug adverse experience-related complaint arises.

Finally, lifecycle management and regulatory filing are fulfilled as a continuous effort during the lifetime of the marketed products. As mentioned before, this usually includes an annual establishment registration and labeler code update, as well as annual Generic Drug User Fee Act (GDUFA) establishment self-identification. Annual reports with minor CMC changes are filed within 60 days of anniversary dates. Any moderate to major CMC change needs an ANDA supplement filing for either Change to be Effective 0/30 days (CBE0/30) or Prior Approval Supplement (PAS). In case of sterility failure, a Field Alert Report (FARs) is required to be filed within 3 days to identify quality defects in distributed drug products. Any known post marketing adverse drug experiences require reporting to the FDA.

The facility contained sufficient and appropriate equipment to meet the requirements. The DMMP obtained an additional lead-shielded laminar flow hood dedicated to aseptic product sampling for QC analysis.

The department expanded the existing facility by two rooms: one as the document storage room and another as the supply room containing cold, dry, acid, base, and flammable containers.

The department acquired the expertise of a regulatory consulting company to assist in reviewing, assembling, and electronically submitting two ANDA applications: [¹⁸F]FDG and [¹³N]NH₃. In addition, investments were made to obtain appropriate cGMP training for the staff and utilize the expertise of a PET quality consulting company to provide a gap analysis and identify areas that required improvement.

The BMC was run by a small number of staff with in-depth expertise of the entire operation. As a result, the staff were released from routine production duties to assist with producing necessary data and standard operating procedures to meet the cGMP and ANDA filing requirements.

The facility produced on average $100,000/month in revenue from supplying [¹⁸F]FDG and [¹³N]NH₃ for our clinical PET/CT service. The 4-month shut down of the operation resulted in a revenue loss of $400,000.

As a PET drug manufacturer, the BMC is subject to a semi-annual drug listing update (every June and December), an annual drug establishment registration (October 1 to December 31), and an annual GDUFA generic drug facility self-identification (May 1–31). The BMC handles these submissions in-house and thus does not incur any additional cost.

BMC holds two active ANDAs submitted in electronic Common Technical Document (eCTD) format. eCTD publishing and ESG submission is outsourced to a regulatory consulting company. The decision to outsource considers the high cost of in-house eCTD publishing setup and maintenance/user training, and its relatively low volume of usage. Minor Chemistry Manufacturing and Controls (CMC) changes that occurred after ANDA approval are reported in annual reports to the FDA. Based on the BMC’s experience, the cost of eCTD publishing and submission service for two annual reports is around $8000.

The cost of annual cGMP maintenance is included in Table 2.

Annual cGMP training is provided to the BMC staff members. The BMC sets training schedules every year by alternating between internal training and an external consultant. Internal training is conducted by senior quality assurance personnel, with updates from regulatory sessions held at the Society of Nuclear Medicine and Molecular Imaging (SNMMI) annual meeting. On average, the cost of training by an experienced domestic consultant is $4000.

As part of our ANDA post marketing commitment and quality system, stability testing and PQIT testing are conducted according to their preset schedules. The costs for post marketing commitment run at $3–5000 annually.

New operational staff are trained by a mix of educational literature, classroom teaching, and supervised on the job training. To initially qualify in performing aseptic manufacturing, an operator must perform three consecutive and successful media fill simulations. Trained operational staff are re-qualified annually by a successful media fill simulation as part of the microbiology assurance.

Periodic audits are an essential element of the BMC’s quality system for self-improvement. A typical 2-day audit by an external consultant costs approximately $5000. As a cost-saving measure, during the same visit, the consultant is usually also contracted to provide annual cGMP staff training.

The cost for maintaining a PET cGMP facility and equipment varies depending on the scope and nature of the maintenance. Preventive equipment maintenance, calibration, or constancy checks are done either in-house by well-trained and qualified chemists or contracted through a third party, either the original manufacturer or specialty service companies. Capital equipment, such as the cyclotrons, and complex analytical equipment, such as the GC, HPLC, and EndoSafe reader, are usually maintained through service contracts, which run at approximately 10 % annually of the original equipment purchase value. If equipment undergoes major repair or other scenarios depicted in the quality system manual, the equipment will undergo performance re-qualification, and the related process or analytical method will be re-validated. We estimate the annual cost for facility and equipment maintenance cost is $250,000 (synthesizer $30,000/year, cyclotron approximately $220,000/year).

The one-time build-out costs in establishing a PET drug manufacturing site are shown in Table 3. More detailed explanations of the cost breakdowns are as follows.

Purchase of a cyclotron, along with two hot cells and two mini cells, are included, in addition to an estimated qualification cost for all the purchased equipment for the site.

An estimated new build-out cost of $2 M is included. However, the cost can vary and be as low as $1 M if retrofitting an existing facility. This dollar amount may vary significantly from one facility to another based on prior use of the facility and includes, but is not limited to, floor reinforcement, plumbing, ventilation and air conditioning, electrical power, and communication, as well as selective demolition and remodel/rebuilding to accommodate a cyclotron.

Based on UCLA’s experience submitting an ANDA application, we estimate a cost of $200,000 for an external regulatory consulting firm to review, compile, and submit the application. The cost can vary significantly depending on the scope of support provided by the external organization and the level of internal resources utilized to prepare the ANDA application and related cGMP documents.

Table 4 outlines the recommended pro forma for a PET drug manufacturing site. The purpose of the pro forma is to demonstrate the cost and revenue associated with establishing a PET drug manufacturing business, and to estimate at which volume of dose production the facility can break even or make a profit. Of note, the cost of the build-out has not been added as part of the annual operating costs. The assumption is that the facility has made this as an upfront investment. If the facility chooses to finance aspects of the build-out, the costs should be added to the pro forma as an annual expense. The costs shown are estimated and extrapolated from UCLA’s cGMP site business model.

A reimbursement rate of $145/dose is estimated and used for [¹⁸F]FDG. This amount is multiplied by the number of daily doses, resulting in the revenue numbers demonstrated in Table 4.

The costs for QC supplies and consumables are expected to be constant for the BMC because the batch production, testing of [¹⁸F]FDG, and ability to provide up to 50 doses can be performed with a single production. Production using kits might have a different cost model.

The UCLA BMC located at an academic medical school is not subject to paying rent to the university. This model may be different for private or other higher education institutions.

Synthesizer costs are estimated at $250,000/synthesizer, depreciated over 7 years. We estimate that a single synthesizer could supply up to 20 doses daily. A second synthesizer may be required to accommodate extra dose productions and a clinic dose schedule.

Major production and QC equipment costs are estimated at $320,000, depreciated over 7 years.

Consulting support, including staff cGMP training, annual audits, and regulatory document submissions, is estimated at $50,000.

The maintenance agreement for the cyclotron is estimated at $180,000. This cost may vary depending on the level of support and services required.

The equipment maintenance agreement is calculated at 10 % cost of the original equipment purchase (obtained suppliers of equipment). Based on an equipment cost of $320,000, maintenance costs are estimated at $32,000.

Personnel costs are estimated at one operations manager, two radiochemists, and one dedicated regulatory support/quality assurance staff. Based on the BMC production, two radiochemists are needed for a single batch production. The personnel cost of production remains constant for 10–50 doses. This model may vary in other institutions, where one radiochemist may meet low dose production demands. The BMC does not utilize a cyclotron engineer and accounts for cyclotron maintenance and support through a cyclotron maintenance agreement instead.