The filling of pharmaceutical products not only has to be time- and cost-effective, it usually has to be done under sterile conditions. There is an increasing trend for the pharmaceutical industry to use isolator technology coupled with automatic filling systems in order to minimise direct human contact with the process. The improved product handling conferred by such systems means that the risk of microbiological and particulate contamination is reduced, thus enhancing the assurance of product sterility, and it also has the potential to protect the operator from toxic or hazardous compounds.
From an engineering point of view, containment is the application of design solutions to prevent uncontrolled escapes of highly potent or toxic compounds from a defined area, while isolation can be defined as the application of engineering solutions to prevent contamination or degradation of clean or aseptic materials and processes.
There is, however, a conflict in the goals, since containment systems usually run under a negative pressure while isolation generally operates under a slight positive pressure.
As the majority of pharmaceutical companies need to compress the time-to-market for new pharmaceutical compounds, toxicological and engineering issues must be handled using a 'multi-tasking' system. The co-operation between customer and filling equipment manufacturer is of paramount importance to assure pharmaceutical companies of proven containment technology.
What, then, are the solutions at hand for the pharmaceutical industry and how can a manufacturer of automatic machines cope with this requirement?
The answer is quite complex. First, there are three possible mechanical interfaces that can be used to integrate a filling machine with an isolator. The most economic and simple solution is to arrange the machine to accept the attachment of an isolator enclosure, keeping the standard machine base (figure 1).
Of course, this option implies a simple design and construction phase since machine and isolator are two separate sections. In this case the interface is located under the processing area.
Another possibility is to design the machine base plate specially to allow a mechanical connection and seals above the machine base itself (figure 2). This solution allows cleaning and draining of the system.
The most complete solution is a so-called 'six-walls isolator' (figure 3), which is a much more complex proposition since a customised design is required. This solution represents the optimum choice in terms of cleanliness, draining and protection against leaks, but involves more precise, accurate and complex design and construction concepts, which must also be considered at the assembly stage.
Particular attention to improved GMP is important for filling:
To reduce manual intervention, the filling machine must be equipped with a series of proving systems, such as a CIP/SIP system for the filling circuit for automatic product change, a check-weighing system that checks 100% of production, and an automatic filling volume adjustment system to ensure a higher filling accuracy with feed-back system to a PC.
One of the most critical aspects is the cleaning procedure. IMA carried out several applications for the US market for filling both liquid and powder forms with semi-automatic cleaning of the machines. The technology used allowed the cleaning of the sterile area while protecting the operator.
The filling machine baseplate had a minimum inclined surface of 2%, and the finish and subsequent treatment of exposed surfaces as well as the reduction of 'dead areas' around gaskets and seals were critical issues to assure good cleaning and avoid cross contamination.
The cleaning operation is divided into various phases: manual washing and drying of the upper machine base and the isolator walls; the filling nozzles can be either dismantled and cleaned separately or clean-in-place.
It is preferable that the dosing units are also washed and sterilised-in-place, to reduce detritus transfer between grey and sterile areas.
Chemical sterilisation of the system is then carried out by introducing the sterilising agent in the vapour or gaseous phase by means of either the air-handling units or nozzles placed inside the isolator itself. VHP (Vapour Phase Hydrogen Peroxide) is typically used nowadays.
As with many processes, in filling machines the important advancement is the continued reduction in manual intervention. This requires a highly advanced level of engineering accuracy and automation, but it does ensure that the capsule or bottle being filled is sterile.