Performance qualification of laminar flow hot-cell for aseptic vial filling during radiopharmaceutical production

M. Brault1,2, C. San1,2, N. Vignal1,3, I. Madelaine2, A. Chane-Kene2, E. Barré2, B. Hosten1,2
1 Université de Paris, INSERM UMR-S 1144, Unité Claude Kellershohn, Institut de Recherche Saint-Louis, F-75010 Paris, France.
2 Service Pharmacie, AP-HP, Hôpital Saint-Louis, F-75010 Paris, France.
3 Service de Médecine Nucléaire, AP-HP, Hôpital Lariboisière, F-75010 Paris, France.

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Introduction
During the automated synthesis of 18F-labeled radiopharmaceuticals, final product is collected in a vial placed in a laminar flow hot-cell (HC) under negative pressure. This working area (PROD) is initially qualified for Grade A and is connected to a Grade B pre-chamber (SAS). The aim of our study is to do a performance qualification of HC with microbiological and particular controls of PROD and SAS.

Methodology
Particle counter integrated to the HC was used for measuring Particle Counting (PC) (≥ 0.5 µm and ≥ 5 µm) in PROD and SAS. PC was evaluated during two different states: in operation during each radiosynthesis and at rest weekly.
Microbiological controls (MC) in PROD and SAS have been performed monthly and consist of surface and air monitoring. 5 and 3 areas have been defined respectively in PROD and SAS for surface monitoring with Count-Tact® plates (CT). Air contamination was controlled in 2 areas for PROD and 1 area for SAS with Trypticase Soy and Sabouraud plates (samples of 1000 liters for 10 minutes). Plates were successively incubated for 3 and 4 days at 32 °C and 22.5 °C. Determination of number of sample and locations was based on French Society of Radiopharmacy guidelines.

Results
PC results in operation (N=17) are mostly compliant with limits (≥ 0.5 µm: NPROD ≤ 3520/m3 and NSAS ≤ 352000/m3; ≥ 5 µm: NPROD ≤ 20/m3 and NSAS ≤ 2900/m3). Non-conformities observed seem to be associated with manipulations in the HC.
88.8 % of PC results (8/9) at rest were compliant with limits (≥ 0.5 µm: NPROD and NSAS ≤ 3520/m3; ≥ 5 µm: NPROD ≤ 20/m3 and NSAS ≤ 29/m3). Non-conformity concerned ≥ 5 µm particles in PROD.
83.3 % of MC results (5/6) were compliant with limits (PROD: air < 1 Colony-Forming Units (CFU)/m3; CT and glove print < 1 CFU; SAS: air ≤ 10 CFU/m3, CT and glove print ≤ 5 CFU). Non-conformity observed was caused by one fungal CFU on a glove print (PROD).

Discussion & Conclusion
Performance qualification of the HC has been done with the instauration of PC and MC in routine. Non-conformities have led to the modification of sanitization program including selection of a sporicidal and disinfectant agent and the use of sterile low particulate wipes. Perspectives for radiopharmaceuticals quality are the implementation of bubble point test to verify the filter integrity after each synthesis and endotoxin detection in radiopharmaceuticals with a colorimetric test.

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