title: Media-fill simulation tests in manual and robotic aseptic preparation of injection solutions in syringes.
abstract: OBJECTIVE
  The purpose of this study was to evaluate the contamination rate of media-fill products either prepared automated with a robotic system (APOTECAchemo™) or prepared manually at cytotoxic workbenches in the same cleanroom environment and by experienced operators. Media fills were completed by microbiological environmental control in the critical zones and used to validate the cleaning and disinfection procedures of the robotic system.
  
  
  METHODS
  The aseptic preparation of patient individual ready-to-use injection solutions was simulated by using double concentrated tryptic soy broth as growth medium, water for injection and plastic syringes as primary packaging materials. Media fills were either prepared automated (500 units) in the robot or manually (500 units) in cytotoxic workbenches in the same cleanroom over a period of 18 working days. The test solutions were incubated at room temperature (22℃) over 4 weeks. Products were visually inspected for turbidity after a 2-week and 4-week period. Following incubation, growth promotion tests were performed with Staphylococcus epidermidis. During the media-fill procedures, passive air monitoring was performed with settle plates and surface monitoring with contact plates on predefined locations as well as fingerprints. The plates got incubated for 5-7 days at room temperature, followed by 2-3 days at 30-35℃ and the colony forming units (cfu) counted after both periods. The robot was cleaned and disinfected according to the established standard operating procedure on two working days prior to the media-fill session, while on six other working days only six critical components were sanitized at the end of the media-fill sessions. Every day UV irradiation was operated for 4 h after finishing work.
  
  
  RESULTS
  None of the 1000 media-fill products prepared in the two different settings showed turbidity after the incubation period thereby indicating no contamination with microorganisms. All products remained uniform, clear, and light-amber solutions. In addition, the reliability of the nutrient medium and the process was demonstrated by positive growth promotion tests with S. epidermidis. During automated preparation the recommended limits < 1 cfu per settle/contact plate set for cleanroom Grade A zones were not succeeded in the carousel and working area, but in the loading area of the robot. During manual preparation, the number of cfus detected on settle/contact plates inside the workbenches lay far below the limits. The number of cfus detected on fingertips succeeded several times the limit during manual preparation but not during automated preparation. There was no difference in the microbial contamination rate depending on the extent of cleaning and disinfection of the robot.
  
  
  CONCLUSIONS
  Extensive media-fill tests simulating manual and automated preparation of ready-to-use cytotoxic injection solutions revealed the same level of sterility for both procedures. The results of supplemental environmental controls confirmed that the aseptic procedures are well controlled. As there was no difference in the microbial contamination rates of the media preparations depending on the extent of cleaning and disinfection of the robot, the results were used to adapt the respective standard operating procedures.
authors.affiliation: Department of Pharmacy, University Medical Center, Johannes Gutenberg-University, Langenbeckstraße 1, Mainz, Germany Irene.Kraemer@unimedizin-mainz.de.
authors.forename: Irene
authors.initials: I
authors.lastname: Krämer
authors.affiliation: Department of Pharmacy, University Medical Center, Johannes Gutenberg-University, Langenbeckstraße 1, Mainz, Germany.
authors.forename: Matteo
authors.initials: M
authors.lastname: Federici
authors.affiliation: Department of Pharmacy, University Medical Center, Johannes Gutenberg-University, Langenbeckstraße 1, Mainz, Germany.
authors.forename: Vanessa
authors.initials: V
authors.lastname: Kaiser
authors.affiliation: Department of Pharmacy, University Medical Center, Johannes Gutenberg-University, Langenbeckstraße 1, Mainz, Germany.
authors.forename: Judith
authors.initials: J
authors.lastname: Thiesen
mesh_terms: D001207:Asepsis / Q000379:methods* / Q000592:standards; D004340:Drug Contamination / Q000517:prevention & control*; D019999:Pharmaceutical Solutions / Q000592:standards; D012371:Robotics / Q000379:methods* / Q000592:standards; D013594:Syringes / Q000382:microbiology / Q000592:standards; D013678:Technology, Pharmaceutical / Q000379:methods* / Q000592:standards
chemical_list: D019999:Pharmaceutical Solutions
keywords: Media fill; aseptic preparation; cleaning validation; environmental monitoring; simulation