Over the last few years the term advanced has been applied to a number of aseptic manufacturing technologies. The 2002 open conference on sterile products co-sponsored by USP and PDA made advanced aseptic processing a discussion point, representing, we believe, the first such discussion in a public forum. At that time, only two advanced aseptic technologies were discussed: isolators and blow-fill-seal. Recently, an advanced technology that fills product into a sealed sterile container has been introduced, and restricted access barrier systems (RABS) have been termed advanced aseptic technology.
We believe that industry and the regulatory community should use the term advanced very conservatively in conjunction with aseptic processing, if it is not to become a commercial catch phrase. Performance limitations must be considered carefully. To avoid further hyperbole and misunderstanding, we propose the following definition:
The following examples would fit this definition:
- Isolators, since they are effectively sealed against the entry of external contamination by means of air over-pressure. Isolators also allow decontamination to be performed in a quantifiable manner, and use gloves or half-suits to separate the human operator and the environment. Finally, all transfers of materials are done through RTPs, decontamination tunnels or pass-throughs.
- Blow-fill-seal systems, provided that direct human interventions are not required during the filling/sealing process.
- Closed-vial filling systems, provided there are no interventions into the critical zone where the filling needle(s) and post-irradiated closure surfaces are exposed prior to filling.
The common theme in these examples is that no direct human interventions are allowed at any time.
One could argue that it is possible to have human interventions in isolators, and in many isolator designs this is true. However, isolators are true separative enclosures with no direct entry by human operators wearing conventional cleanroom garments. All interventions are, instead, made through decontaminated gloves and sleeves or half-suits.Under no circumstances should an isolator enclosure be opened and a gowned operator allowed to work directly within the critical zone.
We believe that this distinction is critical, because studies have shown that gowned operators even when using the best garments and technique may release several thousand colony-forming units into the surrounding environment during each hour of work [1, 2]. Any technology that allows this level of interventional activity, and the potential for contamination associated with it, is too risky to be considered advanced.
Closed-vial filling systems, such as this one by Aseptic Technologies (Les Isnes, Belgium), offer distinct advantages as long as they do not require operator intervention. The line features two main areas. On the left is the loading station, protected by laminar air flow. At right is a Restricted Access Barrier System, in which filling occurs. For filling, a needle pierces the stopper, which is then resealed by means of a laser.
Some blow-fill-seal systems require that operators clear plastic that has solidified on fill nozzles, thereby blocking liquid flow. In this case, blow-fill-seal could only be classified as an advanced technology if, after this type of intervention, the product contact equipment was re-sterilized in place and any potentially affected product segregated and destroyed. Once again, the requirement is clear: if direct human intervention with sterile components or product contact surfaces is allowed, without the ability to eliminate any risk from that intervention, the aseptic process cannot be considered advanced.
Sealed sterilized container systems are advanced, as long as they do not rely upon gowned operators. Obviously, the exterior of the seals must be kept sterile and the filling needles must not be contaminated. For these conditions to exist, neither the seals nor the filling needles can be affected by gowned operator intervention. Closed systems offer significant potential advantages for controlling contamination, particularly those that can be penetrated, filled and resealed without operator intervention.
The question of RABS
Somewhat controversial are RABS, a type of aseptic processing that has lately garnered significant interest. We are encouraged by efforts to provide a suitable working definition of these systems; however, we believe that many, if not most, RABS processes would not meet our proposed definition for advanced aseptic processes. In some RABS designs, operators could open the RABS enclosure if an intervention that could not be conducted through the glove ports were required. In such a case, disinfection using a sporicidal agent has been recommended following the intervention. However, even though this treatment would decontaminate surfaces, it would not address the principal route of contamination, which is personnel-generated and dispersed in the environment.
We are also concerned that such a critical intervention as disinfection by gowned operators could raise nearly as many issues as it endeavors to address. Obviously, residuals from this disinfection procedure and contamination from the personnel performing it would be important concerns. It is not clear to what extent a major line clearance might be required, and what subsequent interventions might be required to restore the system to operation.