Aseptic Production Isolator (API)

12 November 2010

A. Mitidieri Sintetica SA, Switzerland

Integrated production of sterile injectables

Definition of isolator:
An isolator is sealed or supplied with air through a microbially retentive filtration system (HEPA minimum) and is able to be reproducibly decontaminated. When closed it uses only decontaminated (where necessary) interfaces or Rapid Transfer Ports (RTPs) for material transfer. When open it allows for the ingress and/or the egress of materials through defined openings that have been designed and validated to preclude the transfer of contamination. (source: PDA)

Main concepts:
Isolation: the use of an isolator where the objective is to keep the interior free of contamination
Containment: the use of an isolator where the objective is to limit the contamination to the interior
Production of sterile anticancer drugs: “Closed isolator” providing asepsis (isolation) and containment simultaneously

Isolator applications (industry): a world wide data survey
Aseptic filling: 254 installations, 116 in Europe, 150 for liquid filling, 120 in vials the most with a filling speed<100 per minute. The surrounding area is normally class D and the isolator in over pressure (20-60 Pa). The most largely diffused decontamination system employs Vaporized H2O2. The construction type is rigid wall 90% of the cases, with gloves instead of half-suits. (source: ISPE)

The Aseptic Production Isolator (API) for the sterile anticancer drugs filling:

Aseptic manufacturing of micro-batches of vials (1 to 100 ml) and/or syringes (1 to 50 ml)

Product sterility and quality assurance
How the API meets this objective:

  • AISI 316 L mirror polished Closed Isolator with Class A laminar flow in overpressure (1000 change/hour , +60 Pa)
  • Integrated air conditioning system (HVAC)
  • VHP automated decontamination cycle (10exp6 spores log reduction)
  • Automatic monitoring of microbiological contamination, particulate level, temperature, pressure, humidity, air speed, HEPA filters conditions, leak testing. Alarms and interlocks. Recorder and printer
  • Isolator’s volume minimised to have complete accessiblity to all the parts of the aseptic zone
  • Filling circuits including sterilising filter (product contact parts) disposable. No cleaning procedures to avoid cross-contamination.

Filling and stoppering close under laminar flow to immediately close the container

Slow motion operation to reduce the particulate matter
Integrated filling/capping and stoppering unit designed & engineered along with the isolator. Driven by the same PLC of the isolator, minimum change over time required (from vials to syringes 30 minutes). Change of vials size fully automated without isolator sterility loss (5 minutes)
Filling speed around 300 containers per hour

  • Incoming materials through a leak tested and VHP decontaminated double doors airlock.
  • Calibration and validation following IQ/OQ/PQ protocols including Media-fill and decontamination cycle.

Operator & Environment protection:
How the API meets this objective:

  • All the internal surfaces mirror polished with rounded corners without gaskets, easy to clean
    Internal spray wands to clean and sloped fond to perfectly drain the washing liquids in one point, connected to disposable containers in order to avoid any contact with the operator and environment. The waste liquid containers to be burned
    Air recirculating ducts and filters house easy to be cleaned in place with washing liquid closed recuperation system.
  • HEPA filters easy and safe to change (bag in bag out system) in order to protect the maintenance people from cytotoxics exposure. Double HEPA filters (VHP sterilized) on the air exhaust, with push in change system.
  • H2O2 catalyzing system to avoid any environment contamination. H2O2 monitoring system to control the level inside and outside the isolator.
  • Automatic leak test before any decontamination cycle in order to provide operator protection
  • Resistant Hypalon gloves with the use of external under gloves

Reduced operator intervention during filling. (manual loading of the vials/syringes)

  • RTP disposable egress system (Biosafe) for the filled containers to protect simultaneously the operator/environment from the potential container outer surface contamination and the inside of the isolator from the sterility loss
  • Filling machine fully automated integrated into the isolator with slow motion parts and safety devices: no vial no fill (avoiding product on the machine); no stopper no cap ( avoiding contamination risk); vial drop machine stop (avoiding vial break).

End of filling the product contact part (filling circuit including needle) single use to be destroyed. No cleaning no contamination risk.

  • All the safety devices and control systems calibrated and duly validated according IQ/OQ protocols.

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