Have you looked for “stranger things” in your automated PET dose dispensing system? A process and operators qualification scheme
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Many nuclear medicine departments have equipped themselves with automated dispensing systems (ADS) for PET radiopharmaceuticals, in both the operators’ and the patients’ interests. Whether partially or fully automated, to date there is no marketed ADS representing a true “closed-system”. Despite the sterile, injectable nature of ready-to-use radiopharmaceutical drug solutions manipulated by these systems, neither manufacturer’s recommendation nor literature report was found about specific qualification of the process’ sterility, or about operators’ qualification on these dispensing systems. We set up a master plan validation in a radiopharmacy equipped with Trasis Unidose®, including: 1) monthly process-simulating media-fill tests and microbiological contamination assessments of the ADS surfaces; 2) initial and periodic qualification of the operators. The microbiological qualification consisted in surface biocontamination assessment on critical zones with Tryptic-Soy agar. The operator qualification consisted in the evaluation of the operators’ knowledge and skills for using the ADS.
This study highlighted a minor, handborne microbiological contamination on our first assessment, that corrective actions solved. We therefore decided to brief our operators once a month on microbiological control results, hygiene and good practices, with the support of the present case illustrating the biodecontamination efficiency.
As the automation of PET monodose conditioning process still implies human intervention for material preparation and manual biodecontamination, this study illustrates that initial and periodic qualification of the environment and the conditioning process of ADS, including microbiological qualification and operators’ qualification, are needed to meet specifications.
KeywordsPET Radiopharmaceuticals Qualification Dispensing system
Automated dispensing system
European Association of Nuclear Medicine
Food and Drug Administration
Good Manufacturing Practices
High Efficiency Particulate Air
International Organization for Standardization
National Institutes of Health
Pharmaceutical Inspection Co-operation Scheme
The expanded use of positron-emission tomography (PET) and the intercurrent market authorizations of new PET radiopharmaceuticals implied optimization of their dispensing and administration, in both the operators’ and the patients’ interests. Since many evidences showed substantial benefits in radioprotection for the operators in terms of dosimetry, many nuclear medicine departments have equipped themselves with automated dispensing systems (ADS) (Covens et al. 2010). Most of the validations found in the literature consist in monitoring physico-medical parameters such as operator dosimetry and accuracy and/or precision of dose activities measurements through dose calibrators (Lecchi et al. 2012; O’Doherty et al. 2014). Whether partially or fully automated, to date there is no marketed ADS representing a true “closed-system”. For instance, the Trasis Unidose® features a cartridge-filling step which is automatically operated under an open, virtual ISO4.8 system, whose performance is obviously critical for maintaining the microbiological quality of the drug solution. Furthermore, in many radiopharmacies and nuclear medicine departments, the ADS is installed in a non-classified room. Still, despite the sterile, injectable nature of ready-to-use radiopharmaceutical drug solutions manipulated by these systems, neither manufacturer’s recommendation nor literature report was found about specific qualification of the process’ sterility, or about operators’ qualification on these dispensing systems. The basic International Standard Organization (ISO) standards for controlled environment, and the Good Manufacturing Practices (GMP) for production of injectable solutions, still apply to these ADS (ISO n.d.; EudraLex n.d.). A preliminary risk analysis was therefore led in our department prior to the ADS setup and highlighted the microbiological contamination risk could be significant.
The aim of this work was to establish a practical, methodological guideline to help the dozens of Nuclear Medicine centers already equipped with such an ADS (and those intending to) for their routine microbiological qualification and operators’ qualification, based on our practical experience.
Inspired by guidance for qualification of small-scale PET radiopharmaceutical synthesis modules, and in respect with the Pharmaceutical Inspection Co-operation Scheme (PIC/S), the European Pharmacopeia and the Food and Drug Administration (FDA) guidance, we set up a master plan validation in a radiopharmacy equipped with Trasis Unidose®, including: 1) monthly specific process-simulating media-fill tests (MFT) and microbiological contamination assessments of our ADS surfaces; 2) initial qualification and yearly requalification of the ADS operators (Aerts et al. 2014; PIC/S n.d.; Food and Drug Administration CDER CGMP 2012). The first six-month follow-up period already showed the importance of implementing and long-term pursuing such a process to ensure the continuous performances of the ADS and good practices application.
Description of equipment
Qualification was performed on a Unidose® dispenser (Trasis) placed in an adapted shielded cabinet equipped with gloves and a shielded glass oculus (Trasis). The cabinet features a main ISO7 compartment hosting the ADS. The multidose PET radiopharmaceutical drug is contained in a closed reservoir, part of the ADS. The individual dose is obtained by cartridge filling, that is weight-controlled operated under an open, local ISO4.8 zone ensured by a High Efficiency Particulate Air (HEPA) filter, inside the ISO7 compartment. During this critical step, the radiopharmaceutical drug solution leaks from a 0.22 μm sterile filter and fills the open cartridge, which is hereafter capped in the same ISO4.8 zone, then measured in a dose calibrator and finally dispensed.
Microbiological validation - surface biocontamination assessment
Microbiological validation - media fill tests
MFTs were carried out to evaluate the whole filling process sterility at the end of a routine PET session. To achieve those adapted MFT, a sealed, sterile TS broth vial (Becton-Dickinson) was put in place of the leaded multidose radiopharmaceutical vial, then the dispensing process was initiated. The resulting cartridges were aseptically transferred to TS broth tubes (Becton-Dickinson) and according to the European Pharmacopoeia specifications, placed for incubation 7 days at room temperature and then 7 days at 37 °C under 5% CO2, with daily monitoring of turbidity. Positive and negative control solutions were prepared and incubated simultaneously. MFT was operated by a qualified radiopharmacist, repeated three times each session and followed-up monthly for 6 months. Results were expressed as mean ± sd number of contaminated tubes.
Operator qualification (OpQ)
Surface microbiological contamination data were submitted to a two-tailed Wilcoxon matched-pairs signed rank test. P ≤ 0.05 indicated significance.
Microbiological validation - surface qualification
Microbiological validation – media-fill tests
No microbiological contamination was detected in any TS tube. The media fill test resulted in clear, sterile cartridges (n = 7), validating the process sterility.
Two radiopharmacists, 3 pharmacy residents, 1 pharmacy technician and 13 technologists underwent OpQ by a qualified, experienced radiopharmacist. At the end of OpQ, the staff was specifically made aware of daily biodecontamination importance and general hygiene procedures. The staff successfully qualified with a mean score of 97 ± 2/100, reflecting its adequate knowledge and understanding of procedures and its ability to apply these with only a few or no assistance needed at all following trainings and briefings. As OpQ will be repeated on a yearly basis, personal results are archived to enable a follow-up of the competencies from a year to another.
Initial Trasis Unidose® IQ/OQ/PQ
• Setup check-list
• Network configuration
• Labels data consistency
• Air bubble size
• Cartridge closure
• Requested activity vs filled activity precision
• Internal dose calibrators
• precision vs external calibrated dose calibrator
• Particular qualification
• Microbiological qualification (externalized)
• External dose rate
• PC/Unidose bridge
After setting up our internal qualification plan, we highlighted a minor microbiological contamination on our first assessment, that corrective actions solved and made finally the results conform to GMP. We therefore decided to brief our operators once a month on microbiological control results, hygiene and good practices, with the support of the present case illustrating the biodecontamination efficiency.
According to GMP, active air monitoring should be performed additionally to surface monitoring to complete the microbiological qualification. Yet, active air monitoring in Trasis Unidose® is very limited as the space for positioning an air impactor to sample the classified areas, is very limited itself. The manufacturer comes with its own specifically-designed air impactor system handler for the planned yearly maintenance, but such a device is not sold with the ADS so self-qualification seems hazardous when positioning classical air impactor systems. That’s precisely the reason why we decided not to recommend such a control, but rather to introduce an adapted MFT for the ADS: although not designed to assess any ISO classification area, this MFT not only validates the open-system step for cartridge filling, but also validates the whole-process of cartridge-manufacturing sterility, complementary to surface monitoring.
More generally for any ADS, a monthly microbiological control of surfaces and instruments should be recommended, as well as a media-fill test that should be repeated after each maintenance and/or modification of the dispensing process, in line with the recent EANM guidelines on validation and qualification of processes and operators (Todde et al. 2017).
An initial and yearly operator’s qualification should be established including the whole ADS applications. Regular training and information should be dispensed to the operators, regarding the importance of properly carrying out the biodecontamination of surfaces and instruments.
The automation of PET monodose conditioning process still implies human intervention for material preparation and manual biodecontamination. This study illustrates that initial and periodic qualification of the environment and the conditioning process of ADS, including regular microbiological qualification and operators’ qualification, are needed to meet specifications and answer quality standards, in the interest of the patient’s safety.
TM and PG initiated the study. TM, AM, CF, ET, AG, PG performed the experiments. TM, AM, CF, ET and PG analyzed and interpreted the data. TM, AM and PG wrote the manuscript. PG and BG reviewed the manuscript. All authors read and approved the final manuscript.
Nothing to declare.
Ethics approval and consent to participate
Consent for publication
The authors declare that they have no competing interests.
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